20 June 2024 – Thomas Patterson was on holiday in Egypt together with his wife when he first became sick.
It was the 12 months 2015 and he had no concept that he would make medical history.
But Patterson was lucky. He is a professor of psychiatry on the University of California, San Diego, and his wife, Steffanie Strathdee, is a professor of infectious diseases and epidemiologist at the identical university.
Patterson was infected with Acinetobacter baumannii, which the World Health Organization later declared essentially the most dangerous global pathogen. He was flown halfway all over the world to a hospital in San Diego when his symptoms rapidly worsened. He suffered acute pancreatitis, septic shock and multiple organ failure, amongst other life-threatening complications.
All antibiotics failed. Every conventional FDA-approved medical treatment was swept away like a plague by the bacteria that infested every inch of Patterson's body.
A phage miracle
What ultimately saved Patterson’s life and A. baumannii from further ravaging his body? Bacteriophage therapy.
Bacteriophages, or just phages, are viruses that attack certain bacteria.
And the doctor who personally handled Patterson's case? The couple's friend and colleague, Dr. Robert “Chip” Schooley, a renowned professor of medication within the Division of Infectious Diseases at UCSD.
Schooley is co-director of the Center for Innovative Phage Applications and Therapeutics on the UCSD School of Medicine, where he works with Strathdee.
Schooley was the primary physician within the United States to treat a patient – his friend Patterson – with intravenous bacteriophage therapy for a whole-body bacterial infection.
As antibiotic resistance continues to plague the world with pathogens comparable to the horrific A. baumanniiPhage therapy has experienced a relative renaissance, because it was already used on a big scale within the pre-antibiotic era.
“People have gone back to an old concept of bacteriophages,” said Dr. William Schaffner, a professor of infectious diseases at Vanderbilt University School of Medicine in Nashville. “We all know viruses. … COVID, flu and measles can infect us, but there are viruses that can also infect bacteria.”
The current status of phage therapy
Although microbiologist Felix d'Hérelle discovered bacteriophages within the stool of patients with Shigella – the pathogen that causes dysentery – over a century ago, there haven’t been many clinical studies to check their effectiveness.
“Currently, most of the work on phages is done outside the context of clinical trials and is 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 dosage is… what the best routes of administration are… the immune responses to phages or what causes them to lose their activity.”
The FDA in 2019 approved the first US. clinical study on phage therapy. It can be being conducted on the University of California in San Diego.
“For a long time, people didn't understand at what microbiological stages bacteria are killed. Each phage only kills a certain proportion of bacteria. They don't kill as many bacteria as antibiotics,” Schooley said.
This highlights top-of-the-line facets of bacteriophage therapy: its specificity. Antibiotics cannot distinguish between the healthy bacteria in your body – for instance, in your gut – and the pathogens which can be harming you.
“An antibiotic works against the harmful strep bacteria that are causing your sore throat. However, the effect of that antibiotic is felt throughout your body … thereby promoting antibiotic resistance in the bacteria in your intestinal tract,” Schaffner said.
When properly prepared, phages can distinguish with astonishing precision.
Phage preparation
To be certain that the bacteriophages given to patients attack only the bacteria that cause their disease, the phages are grown within the laboratory in bottles with live bacteria.
Like viruses, phages are considered non-living entities that shouldn’t have cells and may only grow by constantly infecting living bacteria. In the identical way, a virus stays energetic by being transmitted between hosts – whether those hosts are humans, animals or, within the case of malaria, even mosquitoes.
Normally, phages die after killing their host bacteria – a process called the lytic cycle – which releases the contents of the bacteria, including the newly formed phages.
The released phages can then attack neighboring bacteria by attaching themselves to the cell wall or membrane of one other bacterial host, injecting their DNA into the host, and using the bacteria's internal machinery to provide much more phages.
It's a reasonably sophisticated example of the microscopic warfare that's continuously happening in nature.
For a time, it was difficult to separate phages from dead bacteria since the latter could contain a toxin that might seriously harm or kill humans and animals.
“It is only recently that good techniques have been developed to remove this endotoxin,” Schooley said.
The secret is to search out the appropriate phages, as they have to be tailored to the particular needs of the patient. Unlike a standard antibiotic, which might achieve a hit rate of 70% or more if a patient is barely suspected of getting a typical infection, comparable to staphylococcus.
Schooley explained: “It is unlikely that if you have a phage, you have the right phage in your hand.”
More testing is required to provide an efficient phage “cocktail,” but experience has shown that the additional work is value it.
Phage therapy is more necessary than ever
The COVID-19 pandemic has thrown many phage therapy researchers off course as that they had to focus their energies on treating and containing the pandemic.
The use of antibiotics skyrocketed. But even before that, the excessive use of antibiotics was looming as a crisis.
“There is no doubt that the bacteria that infect us have become increasingly resistant due to our widespread and somewhat inappropriate use of antibiotics both in agriculture and in the treatment of human diseases,” Schaffner said.
Frequent travel across the globe has also contributed to the event of an ecosystem of multi-drug resistant bacteria that now thrive in parts of the world where they didn’t previously exist.
As bacteria became more resistant, people began using antibiotics that attack a wider area, making a vicious cycle of resistance and drug abuse.
“People started paying attention when they realized that bacterial evolution was continuing, but the successful development of antibiotics was not,” Schooley said.
Phage therapy in the longer term
Schooley believes that phages will likely be used more regularly over the subsequent five years to sterilize infected implants, treat recurrent infections in individuals with cystic fibrosis, and even treat urinary tract infections, amongst other applications.
In patients with implants, for instance, clumpy biofilms of bacteria which can be highly proof against antibiotics but at risk of a phage cocktail can form across the joints.
Phages could even reduce the burden of drug-resistant bacteria on the gastrointestinal tract before chemotherapy or alter our microbiome in the event of diseases regarded as brought on by a specific organism.
With the assistance of the UCSD School of Medicine, Schooley is actively contributing to phage research.
“We are working on developing and conducting clinical trials, both those that we design ourselves and those that we participate in and that are sponsored by the National Institutes of Health and commercial companies. We are also trying to make phages available to individuals under the expanded access program that the FDA allows,” Schooley said.
What could decelerate the spread of phage therapy is the perceived lack of profitability amongst large pharmaceutical firms. Large firms often finance the vast majority of clinical trials and hope for a return on their investment.
But major pharmaceutical firms have cut funding for short-acting drugs and used the cash to treat chronic diseases as an alternative.
“A lot of the money spent on drug research has gone into chronic diseases… cancer, heart disease, psoriasis… The ideal drug, for profitability reasons, is one that you have to take for the rest of your life,” Schooley said.
Smaller biotechnology firms often suffer from a scarcity of funding and should fail to finish the essential initial steps before a clinical trial, stopping the FDA from recognizing the total clinical profit.
Due to a scarcity of funding, the essential initial steps before a clinical trial are usually not taken and the FDA cannot gain an understanding of the total advantages of latest products.
“That's the first thing you want to do before you start very large trials … make sure you have the right dose of the drug and that you're giving it at the right time and in the right way,” Schooley said.
This process is short-cut for smaller firms that don't have a variety of money to spend, leading to smaller studies that don't produce essentially the most promising results. And even when those results are positive, the corporate may exit of business and the outcomes are lost.
“All of these studies are either not done scrupulously, or if they are done, this is often the case,” Schooley said.
Although many who need a real breakthrough in phage therapy don't exactly have the essential money, one biotechnology company caused a stir earlier this 12 months.
In March 2024BiomX, which develops each natural and engineered phage cocktails, has acquired Adaptive Phage Therapeutics to form a brand new company. As a part of the acquisition, BiomX planned to sell $50 million value of stock in the brand new company to fund a phage cocktail called BX004, which is meant for a Phase 2b trial to treat chronic infections in cystic fibrosis patients.
The results of the cocktail’s Phase 2b study are expected within the third quarter of 2025.