What’s Old is New: Bacteriophage is a Therapy That May Combat Antimicrobial Resistance

Bacteriophage, or phage as it is more commonly known, has a long history dating back to the early 20th century. French-Canadian microbiologist Félix d'Hérelle discovered the virus while he was working in the Pasteur Institute in France. The name he gave it is loosely interpreted as bacteria eater.

Bacteriophage is a duplodnaviria virus that infects and replicates within bacteria and archaea. It has been described as looking spider-like with multiple legs with a long tower structure in its center. (see the image below.)

The image on the left details the anatomy of bacteriophage, and the right image shows its mechanism of action for destroying bacteria.

Image courtesy: Guido4, CC BY-SA 4.0 <https://creativecommons.org/licenses/by-sa/4.0>, via Wikimedia Commons

“It has these receptors, which are landing pots that bind to specific bacteria,” BiomX CEO Jonathan Solomon, said. “One of the advantages of phage is being very specific. Phage for one is not going to affect another type of bacteria—unlike broad spectrum antibiotics. And inside the [bacteriophage] capsule, there's a deadly payload. So basically, when the phage finds its prey—a bacteria—it injects its DNA, and then hijacks the bacteria.”

Western and Eastern medicine diverged on the therapy many years ago. Whereas, the Eastern Bloc countries and the Soviet Union committed to bacteriophage, the west developed antibiotics. As such, bacteriophage was dismissed and largely forgotten by western medicine. It’s development and study laid dormant for many years with very few labs working on it in the west.

A Dire Medical Case Leads to Bacteriophage Treatment
In 2015, psychiatrist Tom Patterson and his wife, Steffanie Strathdee, who is an epidemiologist, were on vacation in Egypt when Tom became violently ill. His condition quickly deteriorated, and he became delirious experiencing vivid hallucinations. Steffanie called their travel insurance company who commissioned a lear jet to fly them to Frankfurt, Germany to another hospital a few days later.

Patterson went into a coma and was placed on a ventilator. At his worst stage, his body was sucking calcium from his bones, muscle was being eaten to generate energy in order for him to survive, and he was on the verge of kidney failure.

They performed an endoscopy and realized he had an abscess in his abdomen, a pseudo cyst the size of a football that was infected with Acinetobacter baumannii, a multidrug resistant (MDR) pathogen that can be very difficult to treat.

Initially, 3 antibiotics were administered, but after 2 weeks, none of them resolved the Acinetobacter baumannii infection. He was flown back to the US, and after several ups and downs in Patterson’s condition, Steffanie investigated other options and came across bacteriophage.

After a series of conversations with clinical investigators, the FDA, and the Navy, the Pattersons were granted a compassionate use for bacteriophage treatment. Without the treatment being FDA approved, it was required to have special permission to use the experimental therapy in the United States. After his treatment, Patterson’s condition resolved and he made a miraculous recovery. For those interested in learning more about their experience, people can read their memoir here.

The Patterson story was also detailed in filmmaker Bill Mudge’s documentary, Beating Superbugs: Can We Win? The film can be seen here. Contagion interviewed him about his film when it was released.

A Cystic Fibrosis Bacterial Pathogen That Won’t go Away
Acinetobacter baumannii is just one dangerous MDR pathogen, and another, Pseudomonas aeruginosa, is especially worrisome in people with cystic fibrosis (CF). This pathogen can colonize in the lungs of people with CF, and is often something that can kill these patients, especially if antibiotics prove to be ineffective. 

For people with CF, they live with this concern in the back of their minds. CF patient advocate Gunnar Esiason has been living with Pseudomonas aeruginosa his whole life, and he has been dealing with these types of infections periodically through the years.

During his senior year of college, Esiason was struggling with a severe respiratory infection with Pseudomonas. And while Esiason fought the previous infections successfully with antibiotics, this particular bout felt different. His health, as he describes it, was in a “free fall.” He says it felt as if he was in end stage illness and his lungs were overwhelmed with Pseudomonas. During this period which lasted for years, he had many days where he experienced a variety of issues including reoccurring fevers, multiple antibiotic IV treatments, and fatigue so bad he could barely get up to brush his teeth.

Esiason was able to recover, and the development of a new CF therapy has kept him mostly healthy. He is now 32 years old, married, and has a young son—yet he still worries about Pseudomonas which remains in his lungs.

“We are grateful that CF is very much a manageable condition, but I know in the back of my mind, I have run my antibiotic list through to the end,” Esiason said in a previous interview with Contagion.

Solomon’s BiomX has developed its BX004, an investigational bacteriophage therapy, that is being studied for treatment of chronic Pseudomonas pulmonary infections in CF patients.

Solomon says his company wanted to address the unmet need for people with CF like Esiason.

“These patients are taking a ton of antibiotics just to keep the bacteria at bay and are slowly deteriorating,” Solomon said. “Now, it is quite horrendous because these patients basically, you know, if their lung function deteriorates many times, they are not even eligible for lung transplants because they have a drug resistant bacteria that can emerge anytime.”

The company reported results of its phase 1b/2a trial earlier this year. “We saw quite a dramatic effect of phage therapy on this resistant bacteria,” Solomon stated.

They performed a small study, where 2 patients received a placebo, and 7 patients received treatment. “On average, we've saw something like a 95% reduction in the bacterial burden after such a short treatment duration,” Solomon said. He says this was quite serendipitous, especially considering these patients had stopped responding to antibiotics.

BiomX is committed to getting their investigational therapy through clinical trials and they see a potential path toward regulatory FDA approval. They are expecting the next readout for data in September, and if the data shows BX004 is efficacious and safe, they expect to go into the next phase of clinical trials.

Contagion spoke to Solomon who offers further insights on the therapy and their trial results.

What’s Next?
Antibiotics continue to be a cornerstone of western medicine. Just this past May, the FDA approved Innoviva’s antibiotic, sulbactam-durlobactam (Xacduro), for treatment of hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) caused by Acinetobacter baumannii for patients 18 years of age and older.

Still there are thousands of patients who may benefit with bacteriophage. And in both the Patterson case and in people with CF, there is hope that people who have bacterial infections and have developed MDR may have another treatment option.

It remains to be seen if biopharmaceutical companies are able to bring bacteriophage to market. There are clinical trials underway in several countries to evaluate the efficacy of phage therapy. And a complementary, two-pronged strategy in terms of treatment utilizing antibiotics and bacteriophage could benefit clinicians and their patients.