Bacteriophages in nature
Derived from the Greek words meaning "bacteria eater," bacteriophages are abundant everywhere — on land, in water, within any form of life harboring their target. According to Forest Rowher, PhD, a microbial ecologist at San Diego State University, and colleagues in their book
Life in Our Phage World, phages cause a trillion trillion successful infections per second and destroy up to 40 percent of all bacterial cells in the ocean every day.
Thousands of varieties of phage exist, each evolved to infect only one type or a few types of bacteria. Like other viruses, they cannot replicate by themselves, but must commandeer the reproductive machinery of bacteria. To do so, they attach to a bacterium and insert their genetic material. Lytic phages then destroy the cell, splitting it open to release new viral particles, which in turn infect more bacteria.
History of Phage Therapy
Though the original discoverer of bacteriophages remains a matter of debate, it's widely accepted that in 1915, Frederick Twort, a bacteriologist from England, was the first to suggest that it was a virus that was responsible for previous observations of a "factor" that killed bacteria. Two years later, Felix d'Herelle, a microbiologist at the Institut Pasteur in Paris, picked up where Twort left off and first proposed phages as a therapy for human infections. The first known therapeutic use of phages occurred in 1919, when d'Herelle and several hospital interns ingested a phage cocktail to check its safety, then gave it to a 12-year-old boy with severe dysentery. The boy's symptoms cleared up after a single dose and he fully recovered within a few days. Yet d'Herelle didn't publish his findings until 1931.
In the 1920s and 30s, researchers around the world continued to study and test phages for their ability to treat bacterial infections in humans. However, most of the results of those studies were published in non-English journals and therefore did not immediately spread to Western Europe and the U.S. In the 1940s, the pharmaceutical company Eli Lilly produced phages for human use in the U.S., and they were marketed to treat a range of bacterial infections, including in wounds and upper respiratory infections. But it was suspected that the phages didn't work all that well, partly since they were improperly stored or purified, and it was not recognized at the time that many phages were highly selective about the kind of bacteria they infected. Phage therapy fell out of favor in the U.S. and most of Europe with the advent of antibiotics. Only in regions where antibiotics were not as easily accessed — namely what is now Russia, Poland and the Republic of Georgia — did phage therapy and commercial production continue. However, the phage studies conducted in these regions continued to be non-randomized and uncontrolled, and thus empirical data is still lacking to show that phage therapy was effective.
Phage Therapy Now
Western scientists "re-discovered" phage therapy in the 1980s. Since then, the growing threat of antibiotic-resistant bacterial strains has continued to further interest in phage therapy as a potential alternative. In the 2000s, human experiments began again and data from the first phase I clinical trial in the U.S. was published in 2009. That trial tested the safety of a cocktail of phages specific for E. coli, Staphylococcus aureus and Pseudomonas aeruginosa in 42 patients with chronic leg ulcers. Since it was a phase 1 trial, the study only analyzed safety, not clinical outcomes. No adverse events related to the phages were reported.
Another recent randomized, double-blinded, controlled trial took place in the UK, where researchers tested six bacteriophages in patients with chronic ear infections caused by P. aeruginosa. The amount of bacteria significantly decreased in the treated group, those patients also reported that their symptoms eased and there were no adverse events due to treatment. In 2014, researchers in Belgium launched a small clinical trial to test phage therapy in burn victims whose wounds are infected with E. coli or P. aeruginosa bacteria. The results have not yet been fully published, but there were no safety issues reported.
At Yale University, a bacteriophage taken from a local pond was recently used to treat a life-threatening bacterial infection in an 80-year-old man's chest. That case, described in the May 26, 2016 issue of
Scientific Reports, is similar to the UC San Diego treatment of Tom Patterson, but only in the sense that they both used bacteriophages. Success in the Yale case appears to have relied upon the conversion of the bacteria (Pseudomonas aeruginosa) to an antibiotic-sensitive strain.
Until the 2016 case of Tom Patterson at UC San Diego Health, very few, if any, patients in the U.S. have received intravenous phage therapy to directly kill multi-drug resistant bacteria, especially since the advent of antibiotics.
Phages may help overcome the main drawbacks to today's antibiotics. Antibiotics are broad spectrum, meaning that in addition to killing the nefarious species causing infection, antibiotics also destroy many beneficial bacteria making up a person's microbiome, and that can have a variety of short- and long-term health effects. Bacteria also replicate quickly and the selective pressure of antibiotics encourages the emergence of antibiotic-resistant strains.
In contrast, phages are very specific about the bacteria they infect, so the collateral damage to other bacteria or human cells is minimal. Though bacteria can develop resistance to phage (they can eventually shed the surface receptors that phages use to dock and enter the cells), the risk is low. What's more, since there is a nearly inexhaustible supply of phages in nature, if resistance does occur, researchers can now find new phages that use other receptors, as they did in Tom Patterson's case. Such an approach can be expedited with the use of phage libraries. Finally, antibiotics take years to develop, whereas a phage cocktail can be identified and matched to a patient's specific bacterial infection and purified within a matter of days, making personalized phage therapy-on-demand a potential reality in the future.
Given that phage therapy testing to date has largely been observational, or conducted in small, non-randomized trials, researchers don't yet have the full picture of how it works and the potential risks. They don't yet know the extent of potential short- and long-term side effects of phage therapy. Decades of anecdotal reports from Russia, Poland and the Republic of Georgia, as well as preclinical studies in animals, indicate that phage therapy is likely safe for most people, at least when applied topically to the skin. Given the lack of controls and transparency, however, it's also possible that side effects have been underreported.
Septic shock is the main worry for doctors considering phage therapy. That's because many types of bacterial cells release endotoxins when broken up by phages, which can lead to an overwhelming immune response and organ failure. Yet this is also a concern for some currently available antibiotics. There was no evidence of endotoxins causing septic shock in response to phage therapy in Tom Patterson's case, and septic shock has not been widely reported through the many decades of phage therapy in Eastern Europe.
Finally, phages are able to transfer DNA from one bacterium to another, in a naturally and commonly occurring process known as transduction. Phage manipulation and engineered introduction could theoretically introduce new virulence factors or toxins to already pathogenic bacteria, or convert non-pathogenic bacteria into pathogens. However, this issue can be overcome by pre-selecting phages that have been carefully screened for toxins and virulence factors — an effort that can be facilitated by using ever-expanding phage libraries that several teams are currently developing around the world.
The main challenges to phage therapy are 1) doctors need to know exactly which bacterial strain is causing the infection and 2) they must have several phages that specifically target that strain readily available, ideally from a large phage library that can be screened for a suitable phage cocktail that matches the bacteria. Compounding the latter problem, most pharmaceutical companies are reluctant to dedicate resources to phage therapy development and commercialization. That's because phage therapy is almost 100 years old, making it difficult to patent and generate revenue to justify the initial development costs.
Lack of regulatory approval for phage therapy is also an issue. Phage cocktails need to be customized for each patient's infection and constantly adjusted as the bacteria evolve and develop resistance. Regulatory agencies such as the US Food and Drug Administration (FDA) currently lack streamlined review and approval mechanisms to accommodate personalization and flexibility on a large scale.
Future of Phage Therapy
Diagnostic innovations that take advantage of genomic sequencing and mass spectrometry may soon meet the need for rapid and accurate bacterial identification. Phage therapy's second hurdle, the need for readily available phages, may eventually be met in part by the U.S. Navy Medical Research Center and other teams around the world, who are currently building phage libraries.
Looking further ahead, other technology advances may help make phage therapy even more specific and help with the patent problem. For example, phages could eventually be engineered using CRISPR/Cas9 gene editing techniques to kill only antibiotic-resistant bacteria. Companies then might be more likely to obtain patents on unique phage or phage cocktails, making them a commercially viable investment.
Whatever the future holds for phage therapy, most experts agree that phage therapy will never completely replace antibiotics. Instead, this approach may be used in combination with antibiotics, or as the last line of defense for patients with infections that have not responded to any other treatments. Given the alarming increase in the number of life-threatening multidrug-resistant infections in recent years, the need for investigating the potential role of phage therapy and other alternatives to antibiotics is urgent.
For more information, see:
Abedon, et al. Editorial: Phage Therapy: Past, Present, and Future. Front Microbiol. 2017 Jun 15; 8: 981.
Forde, A., Hill, C. Phages of life - The path to pharma. Br J Pharmacol. 2018 Feb; 175(3): 412-418.