Return of the Phages - a Forgotten Remedy Makes a Comeback

March 5, 2018

These days, we can use social media to find just about anything we’d want—apartments, jobs, the latest viral videos…or even a virus-based treatment for bacterial infections.

Last November, a father desperate to save his daughter, Mallory Smith, from an antibiotic-resistant bacterial infection sought an experimental treatment: phage therapy. He had read a news article about Tom Patterson’s fight with an antibiotic-resistant Acinetobacter baumanii infection. The infection left him in a coma for two months in 2016. His wife, Steffanie Strathdee, Associate Dean of Global Health at UC San Diego, persuaded doctors to try phage therapy after months of no luck with antibiotics. It took three weeks to locate and prepare phages to treat the infection. Three days after the phages were administered, Patterson woke up, and he completely cleared the infection a couple of months later. This was the first time a systemic, multi-drug resistant, bacterial infection had been cured in the U.S. by intravenous phage therapy.

Smith had cystic fibrosis and chronic lung infections were common. Smith’s lung infection was caused by a strain of Burkholderia, an opportunistic pathogen that resisted all attempted antibiotic treatments. In order to cure the infection, she needed a virus that would recognize and kill that specific Burkholderia strain. Smith’s father contacted Strathdee for help. Soon, scientists on Twitter were racing against the clock to locate a virus know as a bacteriophage (or phage for short) that would infect and kill the bacterium.

When Jessica Sacher, a University of Alberta Ph.D. student studying Campylobacter phages, saw the request for phage, her mind started churning. How could scientists get phages to patients quickly? Teaming up with Jan Zheng, an Atlanta-based UX (user experience) designer, they created Phage Directory in a mere three days. Their goal was to provide a catalog of phage researchers and the phages they possess to help get much-needed phages to patients.

Only certain phages recognize a specific bacterium (phage labelled red).(click to enlarge) Figure 1. Only certain phages recognize a specific bacterium (phage labelled red).

But phages are picky—each phage infects a particular bacterial species, and sometimes only a unique strain within that species. Specific structures on the bacterial cell surface such as lipopolysaccharides, teichoic acids and proteins are the signals for phage attachment. "Most of these phages aren’t really well characterized and we don’t know exactly what receptor they target. Ideally we would know that, so we could pick a flagellum-specific phage and a multidrug efflux pump-specific phage, [for example], to target several virulence factors at once," Sacher said.

Though Phage Directory has generated quite a buzz on social media, and phage therapy has been cropping up in recent news as an alternative to antibiotics, early work on phage therapy happened almost a century ago.

The Rise and Fall of Phage Therapy

In 1923, the Georgian microbiologist George Eliava and Félix d’Herelle, a co-discoverer of phage, created the World Centre of Phage Research and Phage Therapy (now named the Eliava Institute) in Tblisi, Georgia. d'Herelle by that point had developed a phage concoction to treat soldiers with dysentery and helped further phage research and clinical applications at Eliava.

These events preceded Alexander Fleming’s serendipitous discovery of penicillin in 1928. With the rising popularity and convenience of broad-spectrum antibiotics, phage therapy soon fell out of favor in much of the world. But phage research continued at Eliava, where patients from all over the Soviet Union were treated for infectious diseases.

Today, many companies have struck up partnerships with Eliava. Phage Therapy Centre for instance, brings foreign patients to Tbilisi for phage treatment of drug-resistant bacterial infections. However, a course of phage therapy costs anywhere from $8,000 to $20,000, and only a handful of patients have made the trek.

In Search of the Right Phage

Transmission electron micrograph of bacteriophage attaching to a bacterial cell at 200,000X magnification.Figure 2. Transmission electron micrograph of bacteriophage attaching to a bacterial cell at 200,000X magnification. Source

Virtually untreatable infections like Smith’s are becoming more common. The FDA permits phage therapy as a last resort, but it requires case-by-case approval. "A patient has to have tried all other antibiotics options before getting approval from the FDA for an emergency investigational new drug," said Sacher. Even so, case-by-case FDA approval is not the bottleneck. Finding the right phage is.

While Patterson was saved by phage therapy, Smith was not so fortunate. She started phage therapy but died the next day. "The optimal time to intervene would have been a couple of weeks ago, before she became critically ill," said Dr. Joseph Pilewski, co-director of the University of Pittsburgh Medical Center cystic fibrosis program, in an interview with STAT news. Had she started phage therapy a few days earlier, the outcome may have been different.

Shortening the time it takes to locate, test, and prepare phages for treatment could save more lives. This is what Sacher and Zheng hope to accomplish by creating Phage Directory. Once the causative organism for an infection is determined, a request can be put through Phage Directory for phages that are potentially effective against the offending organism. The call for phage would also be accompanied by a request for a lab capable of testing and producing therapeutic phages to treat infections.

Each phage culture has to be scaled up and purified before enough is obtained for a course of treatment. Phage preparation has to be done carefully. Endotoxins, such as lipopolysaccharides (LPS) released by gram-negative bacteria during lysis, often contaminate phage preparations. LPS induces a strong innate immune response in humans, so their removal is a critical step in phage therapy preparations.

Because few phage researchers know how to prepare phage for therapeutic uses, Phage Directory aims to identify labs that are able and willing to produce therapeutic phage. The bacterial isolate and phage candidates would be shipped to the testing lab, where the phages’ ability to kill the bacterial isolate will be tested. To increase the odds of eliminating the infection, from 3 to 12 of the most successful phages could be used for treatment.

Finally, the most successful phages would be sent and the patient’s doctors would decide how it would be administered.

Can the Medical Establishment Accept Phage Therapy?

While phage therapy has been used for a century in eastern Europe and Russia, countries outside of this region are just now reconsidering phage therapy for human medicine. In the U.S., biotech companies like AmpliPhi Biosciences and Adaptive Phage Therapeutics (APT) have used phage to successfully treat dozens of patients with bacterial infections and are in the midst of clinical trials for their phage treatments.

Across the Atlantic, Belgium has begun implementing a tailor-made phage treatment approach. Phage preparations are custom made based on a physician’s prescription, much as medications are made to a specific strength and dosage in compounding pharmacies in the U.S. This approach is a huge advancement for phage therapy, allowing physicians to prescribe specific phage cocktails for treatment.

However, phage therapy does have challenges in the public sphere. The thought of injecting or breathing in a mixture of viruses to treat infections may leave some fearful or skeptical about a treatment they have never heard of. "Patients are often deterred by talk of sewage and viruses, and public awareness of the therapy remains low," wrote Tom Parfitt in The Lancet in 2005. The fact that many phages are discovered in sewage (despite being isolated and cultured away from sewage after discovery) may make others question their utility.

Thirteen years later, things are not so different—phage therapy remains relatively unknown outside of the former Soviet Union. "We realized there is no channel for the general public," said Zheng. "We want to create a place for people to learn more about phage therapy." In the future, Zheng hopes that Phage Directory will also serve as a forum for public discussion with phage researchers and doctors. Channels such as Phage Directory or positive stories shared about phage therapy on social media could help showcase the potential of phage therapy as the "next big thing" for treating drug-resistant bacterial infections.

News of these phage therapy developments in the U.S. has stirred up excitement within the phage research community. Many had thought that phage therapy would never be widely accepted as a clinical option for patients in the U.S., but now its future looks much brighter.

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Author: Jennifer Tsang

Jennifer Tsang
Dr. Jennifer Tsang is the science communications and marketing coordinator at Addgene and a freelance science writer. She has completed a Ph.D. in microbiology studying bacterial motility and studied antimicrobial resistance as a postdoctoral fellow.