In this article a pharmacy student interviews a microbiologist to explore phage therapy for antibiotic resistant bacteria.
Interviewee: Jessica Sacher, Ph.D.
Interviewer: Christine Thompson, Pharm.D. Candidate 2023, MBA
Posted 31 January 2021
In the four years prior to entering pharmacy school, I was a pharmacy technician in outpatient and inpatient pharmacy settings. During that time I witnessed many cases where antibiotics did not work against drug‐resistant organisms, and it saddened me that the patients who are infected with these organisms can potentially die when standard antibiotic treatments become ineffective. I also thought about the citizens in third world countries who may not have access to antibiotics, and what is available to them as alternative treatment options.
I am now a P2 pharmacy student learning more about the science of bacterial resistance and this has led me to seek knowledge about alternative antimicrobial therapies. Upon searching online, I quickly found that phage therapy has been an option for decades. This led me to find a curiosity for learning more about bacteriophages and their effects on bacteria.
It turns out that microbiologists and virologists are the main type of scientists that study phages, so I contacted Jessica Sacher, a Ph.D. microbiologist and co-founder of a website called “phage.directory” to see if she knew of any infectious diseases pharmacist researchers studying phages or who have been involved in using them as potential treatment options. She did not know of any, but I still wanted to learn more and she was willing to do an interview with me. Hopefully after I graduate, I can be more involved in phage therapy, sharing a clinical pharmacist perspective on how they could potentially be used as pharmaceutical treatment options. I am hopeful for their full usage approval in the U.S someday.
Here are the questions that Dr. Sacher was kind enough to answer for me to share with the IDstewardship community about phage therapy for antibiotic resistant bacteria…
1. What are bacteriophages and what is phage therapy?
Bacteriophages, or phages for short (sounds like ‘fayge’, rhymes with “page”, though some pronounce it like the end of the word “mirage”), are viruses that kill bacteria. Every kind of living organism has its own set of viruses that infect it (e.g., coronavirus is an animal- and human-specific virus), and bacteria have their own set, which are called phages. Phages are extremely numerous in nature. If you dig around in the dirt or in water or sewage, you can usually find a phage that kills any kind of bacteria you can imagine.
Phage therapy is the practice of actually using phages as medicine (in the same way you’d use an antibiotic), to treat bacterial infections in humans or animals. When our antibiotic arsenal stops working, deploying an antibacterial virus is another way to kill bacteria running rampant in the body.
The best thing about phages is that they each only target a very narrow spectrum of bacteria, unlike antibiotics, which are less targeted and frequently kill broad swaths of bacteria at once. This means we can use phages in a “sniper” strategy to only get rid of the “bad” bacteria, sparing the healthy microbes we want to keep. On the other hand, we have to know exactly what kind of bacteria we’re after, so we can choose the right phage. Thus, there are pros and cons with phage therapy, but ultimately it’s a very promising strategy that is growing in popularity now that antibiotics are failing faster than we expected.
2. How did you get interested in and start working in the field of bacteriophages?
I started working with phages as an undergraduate student at the University of Alberta in Edmonton, Canada, where I am from. I was a microbiology major.
I could not get enough of microbes after learning about fecal transplants curing obesity in mice from my professor; this was around 2008. I wanted some lab experience, and I found a microbiology lab that had a few projects to choose from. One of those was about phages, and studying the ones that infect a food poisoning bacteria, Campylobacter jejuni. At that time, not much was known about Campylobacter phages. I was fascinated that there could be these tiny biological entities (even tinier than bacteria!) floating around that we could actually harness to control which bacteria we had in our body, so I picked that project. From then on, I was pretty hooked on phages and research, and so I did a Ph.D. in that lab and kept working on that project.
3. Is phage therapy something to be combined with antibiotics or would it be expected to use phages on their own?
For most phages, this is something we still don’t know the answer to. Ultimately, it looks like it will depend on the particular phage and the antibiotic, rather than being generalizable.
From the studies that have been done so far, the right combination can sometimes lead to synergistic effects, where phage + antibiotic is better than either alone. But sometimes this backfires, and the presence of the antibiotic makes phage therapy work less well. Several labs are starting to understand the biology behind why certain combinations work, and getting really exciting results. For instance, a phage was found a few years ago that targets Pseudomonas bacteria that make an antibiotic efflux pump, which pumps antibiotics out of the bacterial cell (rendering the antibiotics ineffective). When you combine the phage with those cells, they stop making the efflux pump to avoid the phage. After that, the bacteria are prime targets for antibiotics that they were resistant to before, since their efflux pump is gone (check out Felix Biotechnology and the Turner lab at Yale) for more info on this cool discovery, and how they’re using it to treat patients!
So I think combining phages and antibiotics will end up being the way things go most of the time, but I think as we learn more about how individual phages work, these combinations will be more and more intentional; there will be certain combinations that are known to work well, and others that aren’t used.
4. In which countries is phage therapy being used for infections and which organisms are being targeted?
For about a century, phage therapy has been part of the medical arsenal in the country of Georgia (not to be confused with the US state), which was formerly part of the Soviet Union. There is a phage therapy center there called the Eliava Institute, which treats patients from around the world with phages, as long as they can travel there (not so easy anymore, of course).
There is also a phage therapy center in Poland that has been running for decades, though this one is less integrated into standard medical practices — rather, they use phages only when patients have no other options (often referred to as compassionate use, and done according to the Helsinki Declaration).
Other phage therapy centers are popping up all over the world nowadays, using the compassionate use route. This includes several prominent medical institutions in the US (UC San Diego, Baylor College of Medicine, Mayo Clinic), Europe (Queen Astrid Military Hospital in Belgium), Australia (Westmead Institute for Medical Research, Childrens Hospital at Westmead), and more.
I now run an online directory of phage researchers, developers and practitioners. We have been witnessing a huge sea change since we started it 3 years ago as a small side project. And beyond being practiced at large centers, phage therapy is being tried by individual physicians around the world who come up against a bacterial infection they cannot get rid of.
5. How far along do you think we are in getting bacteriophages used in hospitals in the U.S and Canada as an alternative for antibiotics? Do you think they are the answer to solving the antibiotic resistant crisis?
I don’t think phages are the answer to the antibiotic resistance crisis on their own, but I think they are an excellent arsenal for us to tap into. Even considering them an alternative to antibiotics is not necessarily how I would position phages — I think they should be part of the tool set that healthcare providers have access to.
As far as how close we are to getting there in the US and Canada, right now phages are being used in the US for several patients per year, at a few different centers. But of course, these patients are being treated one at a time on a compassionate use basis; in other words, the phages being given aren’t approved medicines yet. Still, these cases involve extremely well-respected centers, like UCSD, Yale, Mayo Clinic, and the US Navy, as well as biotech companies across the country, like Adaptive Phage Therapeutics, Locus Biosciences, Armata Pharmaceuticals, and Felix Biotechnology. I find this momentum really encouraging, and this has all ramped up in the last 3-4 years.
I do not believe there is phage therapy going on in Canada at the moment, but there is a lot of phage research going on, and patients are starting to ask about it. I think in the US, we could see an expansion of interest in phage therapy in the biotech sector once the presently ongoing phage clinical trials start showing results, assuming they are able to show efficacy. The trouble is, large scale trials with phages have shown to be extremely difficult to do (and COVID-19 is making all that even harder, logistically). That said, even if it takes a few more years to get the large scale clinical trials working, I think we will see more and more academic medical centers starting up their own phage therapy centers in the interim, with more and more patients getting phage therapy on an experimental basis.
6. What are the cons of bacteriophage therapy currently?
Phages are very specific, so the right ones need to be selected for each bacterial target. This is a major challenge (though it is also one of their best features!). It is really hard to know which one will be the right phage without doing an experiment in the lab on each patient’s bacterial isolate first. The other tricky thing is that phage production leads to endotoxin release from bacterial cells, and endotoxin is toxic if we take in too much of it. So phage preparations need to have endotoxin removed before use in patients. This is doable, but you have to have the right equipment, and a way to test that the preparation is safe before giving it to a patient.
Another con is that phages can cause DNA to move around between bacteria — this is a process that happens all the time in nature, and sometimes it leads bacteria to become even more pathogenic. This is actually why cholera is so deadly — once upon a time in history, a phage came along and gave cholera-causing bacteria the ability to make a toxin that causes major damage to the intestine and can be fatal.
We definitely need to keep these risks in mind when considering using phage therapy, and we need to push toward understanding each phage we use, to make sure we know what to expect from it once it enters the body and, later, the environment.
7. Are there any types of phages that could possibly be used against the effects of SARS-COV-2 and COVID-19?
Phages can be useful in the context of COVID-19 for at least two reasons.
First, phages may be able to treat bacterial co-infections in patients with COVID-19. While COVID-19 is caused by a virus, some COVID-19 patients may experience bacterial co-infections at the same time. Over the last few months, Adaptive Phage Therapeutics’ phages have been given to COVID patients who were suffering from antibiotic-resistant
The second way phages can help with the COVID crisis is as vaccines — and again, Adaptive Phage Therapeutics is making headway here. According to their website, they are making phages that display COVID antigens, which could end up being used as a vaccine. Phages are thought to be useful as vaccine delivery agents because they are cheap to make, quick to change in case you need them to (in the case of a new variant, for instance), and they are considered safe to administer.
8. I see that you are a co-founder of a website called phage.directory, can you tell us what it contains, your goals with that website, and the information that would be beneficial for pharmacists and clinicians to find on there?
Yes! I co-founded Phage Directory in 2017 to help doctors find sources of phages for their patients, in the event that antibiotics had stopped working and there was nothing left to do but try phage therapy. My co-founder Jan Zheng created the site after we saw people using Twitter to find phages for a young woman named Mallory Smith, who had cystic fibrosis and not much time left. Since I knew plenty of phage researchers, we figured we would start a directory and notification system so these researchers could be found more easily for future emergency situations like that one. Mallory sadly passed away before the phages could help, which spurred us on. She continues to inspire us to this day, and her family now raises money for phage therapy research, which you can contribute to here.
Shortly after we launched Phage Directory, with the help of coverage from STAT News two weeks later, dozens of phage researchers started signing up to share their phages through our site. Since then, we have helped coordinate phage sourcing for around two dozen emergency clinical cases, some of which have led to saving patients, like this one published recently as a preprint. In this case, phages helped save a 7-year-old girl’s leg from amputation after three months of unsuccessful IV antibiotic treatment.
Since then, we have expanded Phage Directory into a comprehensive community platform for phage researchers and those practicing phage therapy globally to keep up with phage news and research, connect with the right collaborators, share their progress through webinars and articles, overcome the problems they’re stuck on, and of course, find and share phages. We’re still helping coordinate emergency phage alerts (subscribe to alerts, or talk to us about initiating one here). We are also now working with academic medical centers and biotech companies to help them source phages for the long term, so they have a bank of pre-verified phages they can rely on before their patients are in dire need.
What I have learned over the last couple of years is that phage researchers have the phages we collectively need — tens of thousands when you add them up, with more discovered every day, covering many of our important pathogens — but we do not have an understanding of how most of them work, which is a big hurdle preventing their use. This is a big reason clinical trials have been so difficult to do for phages. We now know that there are incredible people in at least 80 countries collecting anywhere from one to thousands of phages each, steadily moving toward understanding each one. My co-founder and I, along with hundreds of phage enthusiasts getting on board, are on a mission to empower phage researchers and medical professionals with the knowledge, tools and connections they need, so that phages become a safety net that doctors and health systems globally can turn to when antibiotics fail.
Where Readers Can Get More Information
On behalf of the IDstewardship community, we would like to extend our sincerest gratitude to Mrs. Thompson for her work to make this interview possible and to Dr. Sacher for taking the time to share her perspective and for the important work she does in the fight against antibiotic-resistant pathogens! #SaveABX
ABOUT THE INTERVIEWEE
Jessica Sacher, Ph.D.
Dr. Sacher completed a PhD in Microbiology and Biotechnology in Christine Szymanski’s lab at the University of Alberta, where she studied the interactions between the gut pathogen Campylobacter jejuni and its bacteriophages. She is passionate about helping the world utilize phages safely and effectively. She believes collaboration among medical professionals, researchers, companies and regulatory bodies is essential for this to happen.
She co-founded Phage Directory as a way to foster such collaborations and to facilitate progress in this field. They track phages, the bacterial hosts they infect, where they have been found, and who is currently working on them.
ABOUT THE INTERVIEWER
Christine Thompson, Pharm.D. Candidate 2023, MBA
Christine Thompson is a Doctor of Pharmacy Student in the Class of 2023 at Cedarville University School of Pharmacy. She have several years of experience working as a pharmacy technician in retail and hospital pharmacy practice settings.
Her goal is to become an infectious disease pharmacist/researcher. She is interested in studying the long-term effects of COVID-19, discovering new anti-infective therapies for patients, and is fascinated on how infectious diseases can be cured without depending solely on antibiotics.
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