June 20, 2024 – Thomas Patterson was on vacation in Egypt with his wife when he first became sick.
It was 2015, and he could have no way of knowing he was going to make medical history.
But Patterson was lucky. He is a professor of psychiatry at the University of California, San Diego, and his wife, Steffanie Strathdee, is an infectious disease professor and epidemiologist at the same school.
Patterson was infected with Acinetobacter baumannii, which the World Health Organization would later name the most dangerous global pathogen. He was flown halfway across the world to a hospital in San Diego as his symptoms rapidly grew worse. He had acute pancreatitis, septic shock, and multiple organ failure, among other life-threatening complications.
All antibiotics failed. Every conventional FDA-approved medical treatment was swatted away like a nuisance by the bacteria invading every inch of Patterson’s body.
A Phage Miracle
What ultimately saved Patterson’s life and eliminated A. baumannii from ravaging his body further? Bacteriophage therapy.
Bacteriophages, or just phages, are viruses that attack specific bacteria.
And the doctor who personally oversaw Patterson’s case? The couple’s friend and colleague, Robert “Chip” Schooley, MD, a distinguished professor of medicine in the Division of Infectious Diseases at UCSD.
Schooley is co-director of the Center for Innovative Phage Applications and Therapeutics at the UCSD School of Medicine, where he works with Strathdee.
Schooley became the first doctor in the United States to treat a patient – his friend Patterson – with IV bacteriophage therapy for a whole-body bacterial infection.
As antibiotic resistance threatens the world with pathogens like the dreadful A. baumannii, phage therapy has seen a relative renaissance, as it was once used extensively in the pre-antibiotic era.
“People have gone back to an old concept in bacteriophages,” said William Schaffner, MD, a professor of infectious diseases at the Vanderbilt University School of Medicine in Nashville. “We're all familiar with viruses. … COVID, influenza, and measles can infect us, but there are viruses that also can infect bacteria.”
The Current State of Phage Therapy
Though bacteriophages were discovered over a century ago by the microbiologist Felix d'Hérelle in the stools of patients with shigella – the cause of dysentery – there haven’t been many clinical trials to test how well they work.
“Right now, most of the phage work that's being done is outside the context of clinical trials, based on people's best clinical judgment,” Schooley said. “We don't have a lot of rigorous clinical trials that tell us what the best doses are … what the best routes of administration are … the immune responses to phages or what causes them to lose activity.”
The FDA in 2019 approved the first U.S. clinical trial on phage therapy. It is also being done at the University of California, San Diego.
“For the longest time, people didn't understand the microbiological stages that killed bacteria. Each phage only kills a certain sliver of bacteria. They don't kill as widely as antibiotics do,” said Schooley.
This highlights one of best things about bacteriophage therapy: specificity. Antibiotics do not distinguish the healthy bacteria in your body – in your gut, for example – from the pathogens harming you.
“An antibiotic will go to work on those bad strep bacteria that are causing your sore throat; however, your entire body will experience the impact of this antibiotic … and thereby promote antibiotic resistance in those bacteria in your intestinal tract,” Schaffner said.
When prepared correctly, phages can discriminate with amazing precision.
Phage Preparation
To make certain that bacteriophages given to patients only attack the bacteria causing their illness, phages are grown in flasks of live bacteria in the lab.
Like viruses, phages are considered nonliving things that don't have cells and can only grow by continually infecting live bacteria – the same way a virus stays active by being transferred between hosts – whether those hosts be humans, animals, or even mosquitoes, in the case of malaria.
The phages usually die off after killing their host bacteria – a process called the “lytic” cycle – which causes the bacteria’s contents, including newly assembled phages, to be released.
The released phages can then attack neighboring bacteria by attaching to another bacterial host’s cell wall or membrane, inject their DNA into the host, and use the bacteria’s internal machinery to produce even more phages.
It's a rather ingenious example of the microscopic war taking place in nature all the time.
For a while, it was difficult to separate phages from dead bacteria, the latter of which could include a toxin that could seriously harm or kill people and animals.
“It wasn't until recently that good techniques came along to be able to clear that endotoxin,” Schooley said.
Getting the right phages is key, as they have to be precisely tailored, unlike a normal antibiotic, which can have a 70% success rate or higher on a patient if you even suspect them of having a typical infection, such as staph.
Schooley explained, “It’s unlikely that if you have one phage, you're going to be able to have the right phage in your hand.”
Further testing must be done to produce an effective phage “cocktail,” but history has shown that extra work is worth it.
Phage Therapy Is More Important Than Ever
The COVID-19 pandemic derailed many of those who were researching phage therapy, as they had to direct their energies to treating and containing the pandemic.
Antibiotic use shot through the roof. But even before then, the overuse of antibiotics was building toward a crisis.
“There isn't any doubt that, as we have used antibiotics so widely, and somewhat inappropriately, both in agriculture and in the treatment of human disease, the bacteria that infect us have become progressively resistant,” said Schaffner.
Frequent travel around the globe has also helped grow an ecosystem of multi-drug-resistant bacteria that flourish in parts of the world where they didn’t exist before.
As bacteria became more resistant, people began using antibiotics that attack more broadly, generating a cycle of resistance and drug overuse.
“People began paying attention when they realized that bacterial evolution has continued, but successful antibiotic development has not,” Schooley said.
Phage Therapy Going Forward
Schooley believes over the next 5 years, phages will be used more to sterilize infected implant devices, treat recurring infections in people with cystic fibrosis, and even treat urinary tract infections, among other uses.
For those with implant devices, say, around joints, clumpy biofilms of bacteria can develop that are highly resistant to antibiotics but are susceptible to a cocktail of phages.
Phages could even reduce the load of drug-resistant bacteria in the GI tract before someone has chemotherapy, or they could even change our microbiome for diseases that are thought to be caused by a specific organism.
With the help of the UCSD School of Medicine, Schooley is actively contributing to phage research.
“We’re working on developing and doing clinical trials, both ones that we design and ones in which we participate that are sponsored by the National Institutes of Health and commercial entities. We're also trying to make phages available to individual people with the expanded access program that the FDA allows,” Schooley said.
What may slow the expansion of phage therapy is the perceived lack of profitability on the part of large drug companies. Large companies often provide the bulk of funding for clinical trials, hoping for a return on their investment.
But large pharma companies have reduced funding for short-term drugs, redirecting that money toward treatments for long-term illnesses.
“A lot of the drug research dollars have gone into diseases that are chronic … cancer, heart disease, psoriasis … the ideal drug from the standpoint of profitability is one you have to take for the rest of your life,” Schooley said.
Smaller biotech firms often suffer from a lack of funding, and the necessary first steps before a clinical trial may not get accomplished, so the FDA doesn’t get to see the full clinical utility.
Because of this lack of funding, necessary first steps before a clinical trial don't get done, and the FDA doesn’t get to see the full usefulness of new products.
“It's the first thing you want to do before you get into very large trials … make sure you've got the right dose of the drug to use, and you're giving it in the right period of time by the right route,” Schooley said.
That process is short-circuited for smaller companies without much cash to burn, which leads to smaller studies that don’t get the most promising results. And even if those results are favorable, the company may go out of business, with the results lost in the fallout.
“All those studies are either not done rigorously, or if they are done, that often dies with it,” Schooley said.
Though pockets don’t seem to run deep for many of those who’d like to see phage therapy really take off, one biotech firm made some waves earlier this year.
In March 2024, BiomX, which develops both natural and engineered phage cocktails, acquired Adaptive Phage Therapeutics to create a new entity. As part of the acquisition, BiomX planned to sell $50 million-worth of the new entity’s stock to help fund a phage cocktail—called BX004—lined up for a phase 2b trial to treat chronic infections in cystic fibrosis patients.
Results of the cocktail’s phase 2b study are expected in the third quarter of 2025.