Banner by Elizabeth Gilfeather

A Viral Conundrum

By Kartik Kannan

Antibiotics. Previously, society was convinced that they were an end-all cure for bacterial infections, and years ago, my high school AP Biology class set out to prove this was still the case. We had exposed multiple types of bacteria to both a standard set of common antibiotics and a set of compounds known as essential oils, and proposed that while the essential oils would have no effect on our tested bacteria, the antibiotics would prove their high efficacy.

However, we could not have been more wrong. The following day, my classmates had found that while the sample bacteria were impervious to many of the antibiotics we had tested, the same bacteria were significantly more susceptible to the essential oils. At the time, this revelation shook me to my core. After all, I had grown up thinking that antibiotics were powerful compounds that could eradicate bacteria with ease. Yet in front of me was evidence that this was not the case. 

Filled with curiosity from this newfound discovery, I sought to answer one question: if antibiotics are not effective in treating bacterial infections, what is? As it turns out, the answer may lie in a novel bacterial treatment known as bacteriophage therapy. 

To understand why bacteriophage therapy has presented itself as a potential replacement for conventional antibiotic usage, it is imperative to understand the mechanisms behind both forms of treatment. As microbiologists Michael Kohanski, Daniel Dwyer, and James Collins note, most antibiotics function in one of three ways—specifically, they inhibit bacteria’s ability to form cell walls, replicate their genetic materials, or create life-sustaining proteins. However, unlike antibiotics, bacteriophages are not antibacterial compounds. Instead, they are viruses with a simple structure consisting of genetic material surrounded by a protein “coat” and cell-specific attachment sites. The research of Athanasios Kakasis and Gerasimia Panitsa has found that the cell-specific attachment sites are what allow bacteriophages to attach to host bacterial cells and not human cells. From there, bacteriophages inject their genetic material directly into bacterial cells and consequently “trick” these cells into creating large numbers of bacteriophages that eventually destroy the host bacteria from the inside.

Because of their perceived versatility, antibiotics had always been depicted as the end-all solution to bacterial infections. Have a strep-based sore throat? Take some penicillin and breathe easy. What about an ear infection? Take amoxicillin, and the ringing in your ears will soon be gone. However, as noted in the journal Infection and Drug Resistance, this mindset has perpetuated the increasing misuse of antibiotics. Initial usage of antibiotics was effective in eliminating bacterial infections. However, with continued antibiotic overexposure, small numbers of bacteria would experience genetic mutations that would allow for the resistance of the effects of treatment, through the production of proteins that either overcome the effects of antibiotics or destroy the antibiotics altogether. Over time, these surviving antibiotic-resistant bacteria became more prevalent in bacterial infections, and with increased antibiotic misuse, said bacteria would become highly difficult to treat.

This is what makes bacteriophage therapy such an intriguing form of treatment against antibiotic-resistant bacteria. None of the biological mechanisms employed by antibiotic-resistant bacteria to thwart the effects of antibiotics can inhibit the activity of bacteriophages, and with most bacteria unable to recognize bacteriophages’ injected genomic material as a foreign substance, bacteriophages are readily able to kill infectious bacteria. A multitude of studies, such as the in vitro studies led by Mathias Schmelcher et al. and murine models created by Rosanna Capparelli et al., have thusly shown that the use of bacteriophage therapy to treat antibiotic-resistant bacteria is both highly effective and able to cure bacterial infections in living organisms with minimal side effects.

These breakthroughs have come through at a crucial time. In 2019, the Centers for Disease Control and Prevention (CDC) stated there were more than 2.8 million antibiotic-resistant bacterial infections per year in the United States, with more than 35,000 individuals a year dying as a result of said infections. Thus, given the viability of bacteriophage therapy in the face of increasing antibiotic-resistant bacterial infection rates, it should stand to reason that this novel treatment would soon be a commonplace therapy, right?

Unfortunately, this has not been the case. One of the contributing factors to bacteriophage therapy’s lack of commonplace use is the dearth of large-scale clinical trials in human patients. Bacteriophage therapy has only been tested in humans in individual case studies, and all of the five active clinical trials testing bacteriophage therapy have been recently started and are thus nowhere close to yielding any significant results. Given that the efficacy of a novel treatment like bacteriophage therapy must be proven with empirical evidence “from two well-designed clinical trials” in order to received approval for use from organizations like the Food and Drug Administration (FDA), the lack of clinical trials and subsequent results signifies that it is unlikely that the treatment will receive FDA approval any time soon.

And without FDA approval, the likelihood of bacteriophage therapy becoming a commonplace treatment is minute. While speaking with Dr. Mala Kailasam, an internist in an outpatient clinic based in Trenton, New Jersey, I learned that without FDA approval, a treatment “can not be regularly used.” Dr. Kailasam, whose practice sees a high number of patients with antibiotic-resistant, bacterial-based urinary tract infections (UTIs), noted that in her practice, she was limited to treating patients with varying dosages and concentrations of antibiotics until one form of treatment worked, as this was permitted to her under FDA guidelines. While Dr. Kailasam also stated that bacteriophage therapy could be considered as an “off-label treatment” that could be used in hospital settings “in which all other options available to a patient had been exhausted without the easing of symptoms,” this form of treatment was typically not common in hospitals and virtually a non-existent option in outpatient clinics similar to the one she worked in.

As it currently stands, the obstacles to the implementation of bacteriophage therapy as a typical treatment for antibiotic-resistant bacterial infections seem causal. Without results from large-scale clinical trials involving the testing of bacteriophage therapy in humans, the treatment cannot receive FDA approval; subsequently, without FDA approval, medical providers cannot routinely prescribe bacteriophage therapy to infected patients. These revelations led me to come to a potential hypothetical – if results were yielded from the ongoing bacteriophage therapy clinical trials that led to the treatment receiving FDA approval, would medical providers then be inclined to administer bacteriophages to their infected patients?

As it turns out, the answer to that question may also be “no.” Dr. Kailasam noted that as with many new treatments on the market, bacteriophage therapy would likely be priced at significantly higher rates than typical antibiotic treatments. This would be especially problematic in medical settings like Dr. Kailasam’s, where many of her patients who come in with antibiotic-resistant UTIs “often do not have healthcare or are on low-coverage, government-based healthcare,” thus making an expensive bacteriophage treatment unfeasible. And although bacteriophages are viruses that specifically target bacterial cells and not human cells, it is still a distinct possibility that patients may inadvertently conflate the viruses used in bacteriophage therapy with the deadly effects of human cell-targeting viruses. As such, if medical providers fail to effectively describe the benefits of bacteriophage administration, patients may be inclined to reject receiving such a treatment.

These findings present a crossroads of sorts. Prior research has shown the increasing fallibility of antibiotics, yet there are a multitude of obstacles preventing bacteriophage therapy from becoming a commonplace treatment option. This begets an important question: what can be done to resolve this conflict?

Surprisingly, the answer lies in both antibiotics and bacteriophages. As Dr. Kailasam shared with me, many of the antibiotic-resistant infections she saw in her practice stemmed from “medical providers prescribing antibiotics for patients without testing the patients to determine their infection’s specific resistances.” Therefore, by ensuring patients are tested before being treated, bacterial infections can be readily cured with existing antibiotic therapies that allow patients to additionally avoid facing ineffective antibiotic administration and painful symptoms.

But as Dr. Kailasam added, every antibiotic ever created eventually sees resistance from the bacteria it is aimed to treat. As such, it is in the best interests of immunologists worldwide to continue working to develop alternative treatments to antibiotics that can effectively treat bacterial infections. With bacteriophage therapy showing viability as an effective non-antibiotic treatment, it is necessary now to yield the evidence needed for bacteriophage administration to be federally approved as a commonplace treatment option for infected patients.

The antibiotic resistance crisis, both in the United States and across the world, is threatening to quickly turn into a global catastrophe. Thus, it is on immunologists, the federal government, medical providers, and the public alike to ensure we approach the crisis head-on. By ensuring the obstacles to bacteriophage therapy are dealt with and that antibiotic usage is done responsibly, we can avoid causing humanity to face a widespread microbial conundrum.