Bacteriophages: A Solution to Antibiotic Resistance

“The Post-Antibiotic Era Is Here. Now What?” was the title of an article by Wired a few years back which talked about how more and more people are getting knocked off by antibiotic-resistant bacteria. In other words, we’ve now entered a “post antibiotic era.” In an article last year titled Can We Kill Antibiotic-Resistant Superbugs?, we talked about how the overuse of antibiotics is one of the main causes behind the rise of superbugs – bacteria that have evolved resistance to drugs. In some places around the world, antibiotics are available over-the-counter so that people might treat conditions like STDs without an embarrassing trip to the doctor. That’s led to problems like antibiotic-resistant gonorrhea. In response, there have been programs like the U.S. government’s Antimicrobial Resistance (AMR) Challenge which saw 350 parties get together recently in New Yawk to address the problem through a number of steps.

The AMR Challenge
The AMR Challenge – Source: U.S. Department of Health & Human Services

While that’s all fine and dandy, it addresses the symptoms of antibiotic resistance, not the problem.

They say that travel is the only thing you buy that makes you richer, and it’s also a great way to find out how other people solve similar problems differently. This past summer we visited the Caucasus to learn about what sort of disruptive technologies are flying under the radar in that region. Turns out quite a bit is happening there, and it was in the country of Georgia that we learned about the powerful properties of bacteriophages, something that just might provide a solution to antibiotic resistance. We sat down to talk with Mr. Rati Golijashvili, a man whose company is making a mint on bacteriophages and thinks it’s just the tip of the iceberg.

What is a Bacteriophage?

Simply put, bacteriophages are viruses that attack bacteria. The name is a play on the words bacteria + phage with the latter coming from the Greek word “phagein” which means to eat. In other words, bacteriophages eat bacteria, and consequently they’re said to be some of the most widely distributed and diverse entities in the biosphere. A picture is worth a thousand words, so here you go courtesy of the WSJ:

A number of microbiologists are said to have discovered bacteriophages, one being a French-Canadian microbiologist named Felix d’Herelle who was exploring India and noticed circles of clean water in the Ganges which locals said might possess magical healing powers. Fast forward a bit through the “who invented what” drama and we get to 1919 when Mr. d’Herelle used phages to treat dysentery in a Paris hospital, what was probably the first attempt to use bacteriophages therapeutically. That’s according to a paper titled Bacteriophage Therapy which goes on to describe how D’Herelle’s commercial laboratory in Paris produced at least five phage preparations against various bacterial infections which were then marketed by a company that went on to become what’s known today as L’Oréal. Then in the 1940s, Eli Lilly produced seven phage products for human use, but with the advent of antibiotics, commercial production of therapeutic phages ceased in most of the Western world. When antibiotics arrived on the scene, bacteriophages were left at the wayside in the Western world and never heard from again. In the Soviet Union, that was hardly the case.

Behind the Iron Curtain

It was at the Pasteur Institute in Paris that Mr. d’Herelle met Giorgi Eliava, a prominent Georgian bacteriologist, and the two of them joined forces to found The George Eliava Institute of Bacteriophage, Microbiology and Virology. Things went pear-shaped in 1937 when Mr. Eliava was executed by Stalin and Mr. d’Herelle returned to France, but the Institute ended up becoming one of the largest facilities in the world for the production of phage therapies with the ability to produce several tons a day. The small country of Georgia had become a big player in the bacteriophage market, and to this day you can buy phage therapies over-the-counter in Georgia. The company that makes these therapies is called Biochimpharm, and they were originally spun out of the Institute back in 1994. Today, they’re growing the business hand over fist and exploring opportunities outside of just human therapeutics.

Biochimpharm

Click for company websiteWe met with founder & CEO Rati Golijashvili at a vibrant startup incubator in Tbilisi where he could barely contain his excitement about the potential of bacteriophages. It’s easy to see why. His father was working on commercializing phages since 1982 and started the first commercial operation in 1994. Five years later, the first phage pharmaceutical was produced just in time for Y2K. Fast forward to today and the company – now named Biochimpharm – has 10 registered products that can be found in more than 500 pharmacies and purchased without the need for a prescription. Some come in the form of “cocktails” which contain multiple phages to address multiple types of bacteria. The most popular phage cocktail is for throat and nose infections, something that other Georgians we spoke to fondly recalled receiving as children.

Phagyo spray from Biochimpharm
Credit: Biochimpharm

About 20% of their market is exports, mainly to post Soviet Union countries. Now they’re developing products outside of therapeutics, primarily in the area of supplements and animal feed additives. Those “antibiotic free” chicken eggs you buy may soon be produced by chickens that are treated with phages.

Bacteriophages in ‘Murica

Given the background story, it’s easy to see why the Americans might be suspicious of miracle viruses developed by the Soviet Union. Behind the scenes, we found dozens of companies that claim to be working on commercializing phages with tens of millions of dollars in investment being channeled into the technology. The aforementioned paper on bacteriophage therapy elaborates on some of the challenges after reviewing over a hundred phage therapy publications.

Firstly, most of the published research is in languages other than English. We all know that most Americans don’t speak anything but the Queen’s English and perhaps a bit of Mexican. Secondly, the research that has been conducted doesn’t quite cut the mustard when it comes to Western expectations. The paper states “additional research is needed in order to obtain rigorous pharmacological data concerning lytic phages, including full-scale toxicological studies, before lytic phages can be used therapeutically in the West.” (Note that this refers to therapeutics, while supplements or animal feed additives may be an easier path to market.) Additional problems with earlier phage research – some of which have been addressed – can be seen in the below table:

In today’s era of “Dr. Google,” people are likely to seek out therapies they may deem beneficial without waiting for the authorities to give their blessing. An article by Stat News last year talks about how the first phage center has opened up in America at the University of California, San Diego. One of the key people behind the new center is co-director Steffanie Strathdee, the associate dean of global health sciences at UCSD whose own husband was saved by a phage. The other co-director is Dr. Robert Schooley, an infectious disease specialist at UCSD who administered the phage therapy to Strathdee’s husband. As soon as word got out, people from all over the world have been asking their help in finding phages to fight bacterial resistant infections. With antibiotic resistance killing 23,000 Americans a year, they have their work cut out for them. (The Eliava phage therapy center in Georgia sees just 15 to 20 Americans every year.)

Conclusion

The bacteriophage investment thesis seems quite compelling. People are already using them in places like Georgia where mothers commonly give their children phage therapies or travelers who venture outside of Georgia take phages with them to fight dysentery. And it’s not like you’re not already full of them, given that phages are regularly consumed by humans in both food and water. As the paper states, “from a clinical standpoint, phages appear to be innocuous.”

Research papers behind the use of bacteriophages for therapy have been extensively published in non-English languages – Russian, Georgian, and Polish – and have largely flown under the radar of the western scientific community. In a future article, we’re going to look at some of the companies starting to emerge with hopes of bringing phage therapies to commercialization in Western markets. If an ambitious Georgian entrepreneur has been operating a profitable bacteriophage business with revenues growing at a 26.75% compound annual growth rate (CAGR) over the past eight years, in the words of Gertrude Stein, there’s definitely some there there.

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