Imagine a scenario where, after contracting a stomach bug, traditional antibiotics prove ineffective. Instead, you consume a vial of clear fluid swarming with bacteriophages—viruses resembling miniature rockets. These harmless viruses target and annihilate bacteria specifically, potentially clearing your infection in just a few days. This possibility is detailed in journalist Lina Zeldovich’s latest book, The Living Medicine: How a Lifesaving Cure Was Nearly Lost―And Why It Will Rescue Us When Antibiotics Fail. The book explores the history and challenges of a longstanding method of battling infections that has often been overlooked by U.S. science in favor of antibiotics.

As bacteria become increasingly adept at resisting antibiotics, some researchers are pivoting back to bacteriophages, gathering them from wastewater and examining their ability to combat pathogens in labs and clinical settings. Current experimental trials are testing phage therapies against formidable adversaries like Shigella, vancomycin-resistant Enterococcus, and a strain of Escherichia coli linked to Crohn’s disease. Meanwhile, the food industry has begun utilizing FDA-approved phage sprays to sanitize products such as lettuce and sausages, though their medical applications have not yet received approval for public use in the U.S.

Scientific American recently discussed with Zeldovich the distinctions between bacteriophages and antibiotics, the storied past of phage experimentation, and the potential future regulations and applications of phage therapy in the U.S.

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[An edited transcript of the interview follows.]

How concerned should people be about antimicrobial resistance?

Several experts I interviewed expressed deep concerns that the next major pandemic could be bacterial due to diminishing effectiveness of antibiotics. A 2019 statistic revealed that every 15 minutes, an individual in the U.S. succumbs to an infection resistant to antibiotics—a fact that astounded me. The COVID-19 pandemic only exacerbated the issue as ill patients required more antibiotics. According to the United Nations, if we don’t find effective alternatives to these failing drugs by 2050, infection-related deaths could escalate dramatically.

What is fueling this resistance? Is it the overuse of antibiotics, or the dependence on a single treatment method?

Resistance is a natural consequence of evolutionary processes: the organisms we target develop defenses. However, the excessive use of antibiotics in both healthcare and agriculture significantly contributes to this problem. In popular media, there’s frequent discussion about unnecessary antibiotic prescriptions. Yet, the larger issue lies in agriculture where antibiotics used on livestock are excreted and continue to impact the environment. They kill off certain bacteria while allowing resistant strains to thrive, which can then enter our food supply and leave us vulnerable to diseases without effective treatments. Hospitals also contribute to the proliferation of superbugs due to their sterile environments.

What are some potential solutions being explored, and how do bacteriophages fit into this?

Bacteriophages, or phages, are viruses that infect only bacteria, using mechanisms that are ineffective against human cells but perfectly suited to invading bacterial cells. These viruses attach to bacteria, inject their genetic material, reproduce inside the bacteria, and burst the host cell. While bacteria can develop resistance to phages, these viruses are also capable of evolving new methods to overcome bacterial defenses. Phages have co-evolved with bacteria for millions of years and are abundant in nature, making them a seemingly endless resource for researchers.

Other strategies include the discovery of new antibiotics from natural sources, though this is becoming increasingly difficult. Artificial intelligence is also being used to design and synthesize new antibiotics in laboratories.

Do you believe bacteriophages are receiving adequate attention and investment?

Bacteriophages are beginning to gain prominence in scientific research. Discovered in 1917, before antibiotics, phages experienced widespread use in the early 20th century as critical antimicrobial agents. However, their application waned in the U.S. after two influential American physicians deemed them unreliable. The advent of antibiotics, which were easier to produce and store, further sidelined phage therapy. However, countries in Eastern Europe and the former Soviet Union continued to develop phage therapy due to frequent antibiotic shortages.

Given the current crisis of antibiotic resistance, there is a renewed interest and increased funding in phage research. This trend has been gaining momentum over the last eight years, according to pioneers in the field.

Would you say that desperation prompted the FDA to consider phage therapies?

That’s an apt description. A turning point was the 2015 case of Tom Patterson, who contracted a resistant strain of Acinetobacter baumannii in Egypt. His wife, Steffanie Strathdee, a scientist herself, sought alternative treatments and discovered phages. With the collaboration of researchers and special approval from the FDA, Patterson was treated with a combination of phages and antibiotics, which ultimately saved his life. This case piqued the FDA’s interest and led to increased funding for clinical trials, which are now more numerous and varied in their stages of development.

What are the current statuses of these trials, and what obstacles do they encounter?

Clinical trials begin with a phase 1 study to demonstrate safety in a small group of participants. The process is intentionally slow to ensure that no harm is done. Phage therapy is still in its nascent stages in the U.S., but there is optimism about its progression. Some European researchers believe that regulatory bodies there have a more flexible approach to approving such treatments.

If phages are administered intravenously rather than orally, could they target a broader array of pathogens?

The full extent of what happens when phages are introduced into the body intravenously is not yet well understood. While they show promise in treating infections of the gastrointestinal and urinary tracts, the dynamics might change when they are administered through the bloodstream.

Is the approval of phage therapy inevitable, or could potential adverse effects derail its progress?

The commitment to phage therapy is strong because there are few viable alternatives. Adverse reactions are a concern with any treatment, but they are especially unlikely with phages if they are properly prepared. Advanced purification methods available today reduce the risk of toxic reactions that were a concern a century ago. Additionally, the interaction between phages and the immune system is an area that requires further study to optimize therapy outcomes.

Is it possible for scientists to engineer phages with specific desired traits, such as enhanced evasion of the immune system?

It’s feasible. By identifying and altering specific genes, researchers could potentially create more effective phages. Additionally, using a mixture of different phages could improve treatment effectiveness. Genetic engineering also appeals to pharmaceutical companies because it allows for the patenting of modified organisms or formulations, which is not possible with naturally occurring phages.

How could regulatory bodies expedite the approval process?

The regulatory landscape is complex. One suggestion is to regulate phages similarly to how flu vaccines are managed. However, the evolving nature of phages and their replication within the body present unique challenges in determining dosage and efficacy. With phages, there may need to be a level of trust in nature’s ability to balance these dynamics.