In my hometown of Pittsburgh, it is not uncommon to read about cutting-edge medical breakthroughs, because Pittsburgh is the home of many innovations in medical science, from the polio vaccine to pioneering organ transplantation. However, medical headlines from Pittsburgh last November weren't heralding a new discovery for once. They were carrying a plea—for a virus.
Phages are weapons of bacterial destruction, but despite recognition of their therapeutic potential for over 100 years, there are zero phage products commercially available to medicine in the United States.
Specifically, a bacteria-killing virus that could attack and control a certain highly drug-resistant bacterial infection ravaging the newly transplanted lungs of a 25-year-old woman named Mallory Smith. The culprit bacteria, Burkholderia cepacia, is a notoriously vicious bacterium that preys on patients with cystic fibrosis who, throughout their life, are exposed to course after course of antibiotics, often fostering a population of highly resistant bacteria that can become too formidable for modern medicine to combat.
What Smith and her physicians desperately needed was a tool that would move beyond failed courses of antibiotics. What they sought was called a bacteriophage. These are naturally occurring ubiquitous viruses that target not humans, but bacteria. The world literally teems with "phages" and one cannot take a bite or drink of anything without encountering them. These weapons of bacterial destruction are exquisitely evolved to target bacteria and, as such, are not harmful to humans. However, despite recognition of their therapeutic potential for over 100 years, there are zero bacteriophage products commercially available to medicine in the United States, at a time when antibiotic resistance is arguably our most pressing public health crisis. Just this week, a new study was published in the Proceedings of the National Academy of Sciences detailing the global scope of the problem.
Why Were These Promising Tools Forgotten?
Phages weren't always relegated to this status. In fact, in the early 20th century phages could be found on American drug store shelves and were used for a variety of ailments. However, the path-breaking discovery and development of antimicrobials agents such as the sulfa drugs and, later the antibiotic penicillin, supplanted the world of phage therapeutics in the United States and many other places.
Fortunately, phage therapy never fully disappeared, and research and clinical use continued in Eastern European nations such as Georgia and Poland.
The antibiotic age revolutionized medicine in a way that arguably no other innovation has. Not only did antibiotics tame many once-deadly infectious diseases, but they made much of modern medicine – from cancer chemotherapy to organ transplantation to joint replacement – possible. Antibiotics, unlike the exquisitely evolved bacteriophage, possessed a broader spectrum of activity and were active against a range of bacteria. This non-specificity facilitated antibiotic use without the need for a specific diagnosis. A physician does not need to know the specific bacterial genus and species causing, for example, a skin infection or pneumonia, but can select an antibiotic that covers the likely culprits and use it empirically, fully expecting the infection to be controlled. Unfortunately, this non-specificity engendered the overuse of antibiotics whose consequences we are now suffering. A bacteriophage, on the other hand, will work against one specific bacterial species and is evolved for just that role.
Phages to the Rescue
As the march of antibiotic resistance has predictably continued since the dawn of the antibiotic age, the prospect of resurrecting phage therapy has been increasingly viewed as one solution. Fortunately, phage therapy never fully disappeared, and research and clinical use continued in Eastern European nations such as Georgia and Poland. However, much of that experience has remained opaque to the medical community at large and questions about dosage, toxicity, efficacy, and method of delivery left many questions without full answers.
Though real questions remained regarding phage use, dire circumstances of prolific antibiotic resistance necessitated their use in the U.S. in two prominent instances involving life-threatening infections. The first case involved an Acinetobacter baumanii infection of the pancreas in a San Diego man in which phages were administered intravenously in 2016. The other case, also in 2016, involved the instillation of phages, fished out of a pond, into the chest cavity of man with a Pseudmonas aeruginosa infection of a prosthetic graft of the aorta. Both cases were successful and were what fueled the Pittsburgh-based plea for Burkholderia phages.
The phages you begin with may not be the ones you end up with, as Darwinian evolutionary pressures will alter the phage in order to keep up with the ongoing evolution of its bacterial target.
How Phages Differ from Other Medical Products
It might seem surprising that in light of the urgent need for new treatments for drug-resistant infections, the pharmaceutical armamentarium is not teeming with phages like a backyard pond. However, phages have been difficult to fit into the current regulatory framework that operates in most developed countries such as the U.S. because of their unique characteristics.
Phages are not one homogenous product like a tablet of penicillin, but a cocktail of viruses that change and evolve as they replicate. The phages you begin with may not be the ones you end up with, as Darwinian evolutionary pressures will alter the phage in order to keep up with the ongoing evolution of its bacterial target. The cocktail may not just contain one specific phage, but a range of phages that all target some specific bacteria in order to increase efficacy. These phage cocktails might also need adjusting to keep pace with bacterial resistance. Additionally, the concentration of phage in a human body after administration is not so easy to predict as phage numbers will rise and fall based on the number of target bacteria that are present.
All of these characteristics make phages very unique when viewed through a regulatory lens, and necessitate the creation of new methods to evaluate them, given that regulatory approval is required. Using phages in the U.S. now requires FDA permission through an investigational new drug application, which can be expedited during an emergency situation. FDA scientists are actively involved in understanding the best means to evaluate bacteriophage therapy and several companies are in early-stage development, though no major clinical trials in the U.S. are currently underway.
One FDA-approved application of phages has seen them used on food products at delis and even in slaughterhouses to diminish the quantity of bacteria on certain meat products.
Would That Humans Were As Lucky As Bologna
Because of the regulatory difficulties with human-use approval, some phage companies have taken another route to develop phage products: food safety. Food safety is a major public health endeavor, and keeping food that people consume safe from E.coli, Listeria, and Salmonella, for example, are rightfully major priorities of industry. One FDA-approved application of phages has seen them used on food products at delis and even in slaughterhouses to diminish the quantity of bacteria on certain meat products.
This use, unlike that for human therapeutic purposes, has found success with regulators: phages, not surprisingly, have been granted the "generally regarded as safe (GRAS)" designation.
A Phage Directory
Tragically Mallory Smith succumbed to her infection despite getting a dose of phages culled from sludge in the Philippines and Fiji. However, her death and last-minute crusade to obtain phages has prompted the call for a phage directory. This directory could catalog the various phages being studied and the particular bacteria they target. Such a searchable index will facilitate the rapid identification and – hopefully – delivery of phages to patients.
If phage therapy is to move from a last-ditch emergency measure to a routine tool for infectious disease physicians, it will be essential that the hurdles they face are eliminated.
Moving Beyond Antibiotics
As we move increasingly toward a post-antibiotic age in infectious disease, moving outside of the traditional paradigm of broad-spectrum antibiotics to non-traditional therapeutics such as bacteriophages and other novel products will become increasingly necessary. Already, clinical trials are underway in various populations, including a major trial in European burn patients.
It is important to understand that there are important scientific and therapeutic questions regarding dose, route of administration and other related questions that need to be addressed before phage use becomes more routine, and it is only through clinical trials conducted with the hope of eventual commercialization that these answers will be found. If phage therapy is to move from a last-ditch emergency measure to a routine tool for infectious disease physicians, it will be essential that the hurdles they face are eliminated.
Shota Kuwahara, a DAWN employee with muscular dystrophy. Ory Labs, Inc. 