Rediscovering phages: ‘We finally have the tools to harness them’
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Antibiotic-resistant infections, which have been on the rise for years, were the cause of more than 1.2 million deaths worldwide in 2019, according to estimates published this year in The Lancet.
In the United States alone, the CDC reported that more than 2.8 million infections are caused by antibiotic-resistant pathogens annually, resulting in at least 35,000 deaths.
Source: Carlos Guerrero
In a report published last year that outlined dozens of traditional antibiotics in development, WHO said it found none that sufficiently addressed drug resistance. There is one nontraditional alternative that has shown promise in patients with resistant bacterial infections: bacteriophages, which are viruses that target and consume bacteria.
“They hold tremendous promise for the superbug crisis, which has worsened under COVID-19,” Steffanie Strathdee, PhD, associate dean of global health sciences, Harold Simon Professor at the University of California, San Diego department of medicine and codirector of the Center for Innovative Phage Applications and Therapeutics, told Healio | Infectious Disease News.
We spoke with Strathdee and other experts about the promise of phage therapy and the process of selecting, shipping and using phages to treat patients.
“Our overuse and misuse of antibiotics has meant that a lot of bacterial infections that used to be treatable are becoming increasingly untreatable, and as a result of that, we need to identify new treatments,” Strathdee said.
Freezers full of phages
Strathdee has personal experience with phages. After her husband developed a highly resistant Acinetobacter baumannii infection during a vacation overseas, he was successfully cured with personalized phage cocktails prepared for him by Texas A&M and ordered from the U.S. Navy, which has been exploring phages as a treatment for returning service members with antibiotic-resistant infections and for biodefense.
According to Strathdee, although phages are still considered an experimental treatment in the U.S., the FDA can approve them on a case-by-case basis in situations so serious that patients are left with limited or no other options.
Phages infect and replicate within bacteria, essentially destroying them. In recent years, as the use of phages has expanded, experts have learned more about their uses.
“There are an estimated 10 million, trillion, trillion phages on the planet — or a nonillion,” Strathdee said. “They are found in soil, they are found in water, under rocks, in our microbiomes. They’re found literally everywhere” — even kitchen sponges, as explained during a presentation at ASM Microbe in 2019.
“If you’re a physician or researcher and you’re trying to source phages for a patient, it would be very impractical to have to go to these environmental sources every single time,” Strathdee said.
Instead, phages that are identified from the environment can be characterized, sequenced, annotated and catalogued.
“One of the best sources of phages that have already been characterized is through the program at the University of Pittsburgh,” Strathdee said. “They have the Cadillac version of a phage library.”
It is one of largest phage collections in the world, if not the largest, and it is run by Graham Hatfull, PhD, Eberly Family Professor of Biotechnology at the University of Pittsburgh, and colleagues.
“We have a collection of over 20,000 phage isolates — 20,373, currently,” Hatfull told Healio | Infectious Disease News.
Hatfull said his team has sequenced roughly 4,075 phages, which shows how they are related and if any of them are likely to be the same, which is rare.
However, Hatfull said the phages are isolated on a relatively small number of bacterial hosts — just eight species — and about half of them, nearly 10,000, were isolated on a single strain of bacteria: Mycobacterium smegmatis mc2155.
Robert T. “Chip” Schooley, MD, who codirects the University of California, San Diego’s Center for Innovative Phage Applications and Therapeutics with Strathdee, noted that interest in phages is picking up.
“We have had around 1,300 requests for advice about phages over the last couple of years, and I’m sure there is a lot more happening that we don’t know about,” Schooley said. “What we do know is that there is a lot of interest in the U.S. and increasing levels of interest at newer phage centers in Belgium and France, as well as more established centers in Poland and Russia.”
He said phages have not been used much in Latin America, although he is scheduled to go to Brazil to work with a colleague in building a phage bank there.
“We’ve had to postpone some time now, but we’re trying to get that set up in Brazil to serve Latin America,” he said.
The process of setting up a phage bank is relatively simple, Schooley said. It is just a matter of getting all of the equipment for collecting, culturing and filtering phage sources.
“It’s really like setting up a regular bacteriology lab but with a little virology on top of it,” he said.
At these labs, phages are stored in large freezers, and they sit waiting for a request come in.
Finding the right phages
When a call comes in requesting phages, experts get to work assessing the patient’s records to determine if they are a fit for phage therapy. Not all of them are.
“Our cases to date are on a compassionate use basis, so the patients are all very different, and the therapy is based solely on the prospects of helping the patient, not on learning how to use the phage therapeutically,” Hatfull said.
Help is available if the patient is truly out of options and has an infection that matches a phage.
“If we are contacted by a physician because they have a patient who is out of treatment options, we ask them to send the isolate to us,” Hatfull said. “We then screen it with a panel of phages, typically about two dozen, and if we have one or more phages that look promising, we test to see if that phage kills the bacteria in the lab and without a high level of survival.”
Hatfull explained that it takes up to 2 weeks for the initial screening and then a few more weeks to test if the phages kill the strain of bacteria efficiently, although it could be longer if the bacteria grow slowly. If there is a good match, the phages are delivered by standard courier services such as the U.S. Postal Service, UPS or FedEx.
Shipping is sometimes complicated by a lack of awareness and fears over a package labeled as a biohazard, Strathdee said.
“At times, we have had problems identifying a courier that would be willing to carry [them],” she said. “But in general, they ship like regular biological materials. They need to be kept at 4°C, so they ship usually on wet ice, and they’re usually also kept away from the light because some are more sensitive to sunlight and ultraviolet light.”
Once phages arrive where they are needed, patients are treated, often intravenously, and physicians wait to see if they have an effect.
Whether or not they work, patients are not usually charged for the cost of the phages, according to Strathdee.
“In the U.S., entities providing drugs or vaccines that are not yet approved by the FDA can recover the cost of producing the material but, until FDA-approved, health care facilities and phage laboratories are not allowed to make a profit by charging more than the true cost of production,” Schooley said. “There are some phage centers operating abroad that do charge for phage access and some of these do make profits.”
Unknown rate of success
According to experts, phages are promising because of how they attack bacteria, which is very different from how antibiotics work.
According to Schooley, the major factor determining if a phage will work are the receptors on the surface of the cell to which phages learn to attach.
“Surface structures on the phage have to fit the ones on the bacterium, and then, once they get into a bacterium, they have to be able to replicate,” Schooley said. “Phages have sort of adapted to replicate better in the organisms that they like to attack, but bacteria have developed all kinds of defensive maneuvers to try to avoid being killed by phages.”
Despite bacteria’s ability to alter surface receptors to stop phages from binding, researchers have had success treating patients. Success rates vary depending on who you ask and how they view “success.” Schooley estimated that the success rate is about 50% in those for whom phages can be found that are active against the organism being treated.
“This is a group of patients who have exhausted all other possibilities for the most part, and any success is one that would not have happened otherwise,” he said.
He said more rigorous clinical trials are needed to better understand how to best use phages and to increase the success rate.
Strathdee emphasized that there are no hard data available on the efficacy of phage therapies — at least not yet.
“We don’t have the numbers on this yet because it varies so much,” she said. “Many of our cases are compassionate use, so, what do you call a success if you clear the person’s bacterial infection, but they still die of their underlying disease?”
“I call that a success,” she said. “But I know that’s not a success to the family because the patient still died.”
Hatfull said there are several reasons why a phage may fail outside of the patient being too sick to survive.
“We see favorable outcomes, either clinically or microbiologically, in a number of cases, but there are also examples where there is no evident benefit,” he said. “Of course, in instances in which phage therapy does not seem to be effective, there are numerous potential reasons, from the most trivial — the phages didn’t survive the shipping — to the more complex [like] neutralizing antibody responses.”
With many lingering questions, the Antimicrobial Resistance Leadership Group (ARLG), which consists of more than 100 experts, and the NIH’s National Institute of Allergy and Infectious Diseases established a task force to conduct an analysis of the use of phage therapy, according to Gina A. Suh, MD, an infectious diseases specialist who established the Mayo Clinic’s phage therapy program.
“The intention was to conduct a careful retrospective analysis of compassionate use data that could provide valuable information for clinicians and inform methods to prospectively collect compassionate use data and the prioritization and design of clinical trials to further evaluate phage therapy,” Suh told Healio | Infectious Disease News. “The other objective of the paper is to be a basic primer to introduce phage therapy to clinicians who may not be as familiar with this mode of treatment.”
According to Suh, most medical providers in North America are not formally educated in the concept of phages as a therapy, much less exposed to clinical cases. Because of this, she and her colleagues divided the paper up into three sections exploring clinical indications, microbiology and pharmacokinetics.
“Each subgroup was composed of multidisciplinary teams to evaluate existing evidence, highlight research gaps and challenges and propose critical research and development steps necessary to achieve regulatory clearance and guide the use of phage therapy,” Suh said.
By answering common clinical questions surrounding phages based on data available from the retrospective review — such as what types of infections phage therapy should be considered for, and if antibiotics should be given concurrently — the team determined that phages have been used to treat a wide variety of infections.
“A one-size-fits-all approach does not work with phages due to their extremely narrow host range and their enormous heterogeneity. Phage therapy therefore often needs to be tailored and personalized for the best outcomes,” she said.
“Phages seem to often work best in conjunction with antibiotics, so phage therapy should be considered as an adjunct to antibiotics, not necessarily an alternative to antibiotics,” she said. “Phage susceptibility testing is very important to help select for the most appropriate phages for a given infection, just as antibiotic susceptibility testing is for antibiotics. Phages also have an excellent safety record and significant adverse events have been rare.”
According to Suh, there is a lot of work left to more precisely understand the “vast complexities of phages” and how best to capture their properties for therapeutic use.
“There are still many unresolved questions regarding dosing, dosing duration, dosing frequency, route of administration, but I expect that the answer to these questions would be different for different situations,” Suh said.
Phage therapy trials on the horizon
According to Strathdee, the future of phages is dependent on clinical trials.
“And I don’t mean just one. It needs to be a series because there are so many different kinds of bacterial pathogens and different underlying health conditions,” she said.
Sources: 1. Strathdee, et al. 2. Murray, et al. 3. Hatfull, G
The ARLG will launch one of the NIH’s first phage therapy trials in the coming months with Schooley as one of the principal investigators, Strathdee noted. The trial will focus on a common bacterial infection among patients with cystic fibrosis (CF), she said.
Strathdee and Schooley noted that there are other patient populations that are good candidates for phage therapy trials, including those with UTIs, prosthetic joint infections or device-associated infections.
Patients with CF, for example, are living longer and are exposed to more antibiotics than ever before, causing bacterial infections in their lungs to become more resistant.
“Many are no longer dying directly of CF. In many cases, they’re dying of superbugs,” Strathdee said.
“By 2050, antimicrobial resistance is predicted to be the world’s biggest killer, killing 10 million people per year, which is greater than diabetes or heart disease,” Suh said. “Phage therapy has the potential to completely change the way infections are treated. It offers an adjunct to antibiotics in an age when the antibiotic pipeline is drying up and we are seeing more and more resistance to conventional antibiotics.”
Not only do phages have powerful and stand-alone antibacterial properties, they also have the potential to help physicians use antibiotics in a much more judicious manner, preserving them, Suh said.
“We’re in the early stages of phage rediscovery,” Schooley said. “We’ve been working with them scientifically for more than 100 years now, but I think we finally have the tools to harness them in a more thoughtful way to be used for medical purposes.”
- References:
- CDC. Antibiotic resistance threats in the United States. 2019. http://www.cdc.gov/drugresistance/Biggest-Threats.html. Accessed Nov. 13, 2019.
- Murray CJL, et al. Lancet. 2022;doi:10.1016/S0140-6736(21)02724-0.
- Suh GA, et al. Antimicrob Agents Chemother. 2022;doi:10.1128/aac.02071-21.
- Weiss B, et al. There are bacteriophages in your kitchen sponge. Presented at: ASM Microbe; June 20-24, 2019; San Francisco.
- WHO. 2020 antibacterial agents in clinical and preclinical development: an overview and analysis. https://www.who.int/publications/i/item/9789240021303. Accessed April 21, 2022.
- For more information:
- Graham Hatfull, PhD, can be reached at gfh@pitt.edu.
- Robert T. “Chip” Schooley, MD, can be reached at rschooley@ucsd.edu.
- Steffanie Strathdee, PhD, can be reached at sstrathdee@health.ucsd.edu.
- Gina A. Suh, MD, can be reached at suh.gina@mayo.edu.
Click here to read the At Issue, "What bacterium is at the top of your list of targets for phages?"
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