The effectiveness of antibiotics against an increasing number of bacterial pathogens has become uncertain due to antimicrobial resistance (AMR). In 2019, over 1.2 million individuals died directly from antibiotic-resistant bacterial infections. If no actions are taken, it is projected that in 2050 the annual death toll from drug-resistant diseases will reach 10 million. The implication is evident: explore alternative treatments or confront a future where formerly curable infections result in preventable fatalities.
Enter: Bacteriophage Therapy
Bacteriophages, also known as phages, are viruses that specifically target bacteria. The use of phages in medical treatment, known as phage therapy, aims to combat bacterial infections. Phages are abundant in various environments, such as soil and the human digestive system, and come in numerous types. Unlike many antibiotics that eradicate both harmful bacteria and beneficial microbiota, phages have evolved to selectively target specific strains or species of bacteria. This targeted approach makes phage therapy an appealing alternative for managing infections, particularly those caused by bacteria resistant to multiple drugs.
Bacteriophage (Electron Microscope)
(Source: Wikipedia)
However, phage therapy has remained on the periphery of mainstream medicine, particularly in Western countries like the United States. It is occasionally approved for compassionate use, which means it can be employed in emergency situations when no other approved treatments are available. The reasons behind this limited acceptance are intertwined with historical skepticism, regulatory and manufacturing challenges, and the inherent characteristics of phages themselves. To establish phage therapy as a widespread practice, significant advancements must occur in addressing these issues.
The Rise and Fall of Phage Therapy in the West
Phage therapy is not a new concept, with its origins tracing back over a century. Felix d'Herelle, a French-Canadian microbiologist, is acknowledged for his role in the discovery and naming of bacteriophages.
(Source: Wikipedia)
However, there is some dispute regarding whether d'Herelle or the British microbiologist Frederick Twort was the true discoverer. Regardless, d'Herelle's utilization of phages to combat bacterial infections initiated international efforts, primarily concentrated in the former Soviet Union, to explore the effectiveness of phage therapy in treating a range of ailments such as typhoid fever and cholera. Early investigations showed promise, although, by today's standards, the experiments often suffered from flawed designs, lacking elements like placebos or control groups. Furthermore, the results were published in non-English journals, limiting accessibility to Western scientists. Nonetheless, phage therapy did gain traction in the United States during the 1940s, as several American pharmaceutical companies manufactured phage preparations to address various infections, including upper respiratory tract infections and abscesses.
Phage Therapy Declines in Western Medicine
Nevertheless, phage therapy gradually lost its popularity in Western medicine due to various reasons. Firstly, scientists expressed doubt regarding its effectiveness. Issues like improper phage storage or purification likely contributed to this skepticism. Early commercial preparations, for instance, contained "preservatives" such as phenol, which had detrimental effects on phages by causing denaturation and inactivation. Additionally, scientists lacked the understanding that phages were highly specific to the bacteria they targeted. Consequently, phage therapies were often employed to treat bacterial infections that were not susceptible to the specific phages used. Furthermore, societal factors played a significant role.
Following World War II, research and utilization of phage therapy persisted in Eastern European countries and continues to this day. Countries like Georgia, Poland, and Russia still consider phage therapy a routine medical practice. However, in Western Europe and the United States, scientists shied away from phage therapy due to its association with the former Soviet Union, especially after the war. The final blow to phage therapy came with the discovery of penicillin. The emergence of antibiotics revolutionized the treatment of bacterial infections and quickly became the global standard.
A Rebirth of Phage Therapy
However, in recent years, phage therapy has undergone a resurgence in the United States. This resurgence has been driven, at least in part, by the increasing threat of antimicrobial resistance (AMR). Dr. Steffanie Strathdee, Associate Dean of Global Health Sciences and Co-Founder and Co-Director of the Center for Innovative Phage Applications and Therapeutics (IPATH)—the first dedicated phage therapy center in North America—at the University of California, San Diego (UCSD), has played a leading role in advancing the phage therapy movement.
A BIG STORY:
Strathdee's involvement in phage therapy can be traced back to a personal experience. In 2015, her husband, Dr. Tom Patterson, a psychiatry professor at UCSD School of Medicine, contracted a life-threatening infection caused by multidrug-resistant Acinetobacter baumannii during their vacation in Egypt. Conventional antibiotics proved ineffective in controlling the infection. "The doctors essentially told us that there were no other options... and we could see him deteriorating right in front of us," Strathdee recounted. With time running out, she diligently searched the internet for any possible solution that could save Patterson. An article about phage therapy caught her attention, and she approached Patterson's doctors with the idea. After obtaining approval from the U.S. Food and Drug Administration (FDA), they agreed to give phage therapy a chance.
The research team collaborated with scientists from the Center for Phage Technology at Texas A&M University and the U.S. Navy to identify bacteriophages capable of killing Patterson's A. baumannii isolate. The search for phages involved examining existing phage libraries (collections of phages previously obtained from various sources) and isolating new phages from sources such as sewage, barnyard waste, and even the bilges of Navy ships. This endeavor proved successful. Patterson's condition began to improve almost immediately after receiving an intravenous phage cocktail, leading to a complete recovery. After spending nine months in the hospital, he was able to return home.
Patterson and Strathdee later published a book called The Perfect Predator, recounting their remarkable journey. Patterson's widely publicized case brought phage therapy research into the spotlight. In recent years, numerous case studies conducted in the United States and Western European countries have emerged, showcasing the effectiveness of phage therapy in treating various multidrug-resistant (MDR) infections, ranging from lung infections in cystic fibrosis patients to urinary tract infections.
Challenges of Developing Phage Therapeutics
Despite phage therapy gaining attention in the field of medicine in the United States, it is not currently a prominent approach. The primary obstacle is the lack of sufficient clinical trials demonstrating its effectiveness. According to Strathdee, clinical trials play a crucial role in establishing the efficacy of therapeutic interventions in the Western medical system, as anecdotal evidence and case studies alone are not considered sufficient.
There exist two categories of phages: lytic and temperate. Lytic phages are characterized by their ability to invade the host cell and cause it to rupture, resulting in the death of the bacterium. On the other hand, temperate or lysogenic phages do not immediately kill the bacterial host. Instead, they integrate their genetic material, which might contain genes associated with antibiotic resistance (AMR) or toxins, into the host cell. While the phage may eventually cause the cell to burst, this does not immediately impede bacterial infection and could potentially contribute to the dissemination of AMR and other virulence genes. Therefore, it is crucial to utilize exclusively lytic phages in phage therapies to ensure optimal outcomes.
Considering that, the procedure of identifying bacteriophages to treat infections can be time-consuming. It typically involves examining phages from existing collections in order to find ones that can eliminate the specific bacterial strain affecting the patient. Dr. Strathdee compares this process to having numerous keys and trying to match them with corresponding locks. According to one study, the time span between requesting phage therapy and actually administering it to the patient ranged from 28 to 386 days.
Nevertheless, there are efforts underway to develop products with a wider range of effectiveness. For instance, Locus Biosciences, a company specializing in engineered phage biotherapeutics, produces drug products in the form of phage cocktails that target more than 95% of clinical strains for four different pathogens: Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus. This approach eliminates the need to culture the patient's bacterial isolate and screen a library for suitable phages, potentially streamlining the process.
Manufacturing and Administrating Phage Therapeutics Isn't Straightforward
In contrast to antibiotics, which gradually decrease in concentration within the body, phages have the ability to multiply. As a result, the number of phages in a patient's system may differ from the initial dose of the phage cocktail administered. The impact of this self-replicating characteristic of phage therapies on treatment effectiveness and the potential for adverse effects remains uncertain. "Pharmacokinetic and pharmacodynamic studies are necessary to determine the fate of phages when a certain amount is delivered through a specific route," explained Strathdee.
Likewise, it is crucial for researchers to verify that the phages exhibit the intended performance within the specific environment they are expected to function in, as stated by Dr. Nick Conley, Vice President of Technology at Locus Biosciences. An illustrative instance would be the use of phages to treat a urinary tract infection (UTI), where their activity in urine is required. There are also significant considerations to bear in mind from a manufacturing perspective. To elaborate, in order to produce phage preparations, the phages are amplified within bacterial hosts—these phages infect the bacteria, resulting in bacterial lysis and the subsequent release of additional phages, thus creating a phage soup with a high concentration. However, as Conley explained, during this process of lysis, various components of the bacteria, such as toxins and DNA, are also released. Before the phages can be administered, for instance, into someone's bloodstream, it becomes necessary to eliminate these components alongside other cellular constituents.
Potential for Bacterial Phage Resistance
Patients typically receive combinations of phages, known as cocktails, which target bacteria using different mechanisms. The likelihood of bacteria developing resistance to multiple phages is lower compared to resistance against a single phage, although it is still possible. Continuous monitoring is necessary for patients undergoing phage therapy to ensure the effectiveness of the phages against the infection.
If the phages become ineffective, researchers need to identify a new set of phages that can combat the pathogen. However, the development of resistance is not always negative. In certain cases, modifications in bacteria that promote resistance to phages can actually enhance their vulnerability to antibiotics. This synergy between phage resistance and antibiotics can contribute to the efficacy of antibiotic treatments.
The Future of Phage Therapy
Despite facing various challenges, the potential for phage therapy appears promising. Strathdee emphasized that the FDA is supportive of phage therapy, and according to Conley, the FDA has taken a thoughtful and reasonable approach to regulating phage therapeutics. The U.S. National Institutes of Health (NIH) has recently granted $2.5 million to 12 institutes worldwide for studying phage therapy.
Clinical trials are currently underway, including a multi-center Phase 1b/2 trial that assesses the effectiveness of a single dose of phage therapy in cystic fibrosis patients who are chronically colonized with P. aeruginosa. Additionally, in July 2022, Locus initiated a phase 2/3 trial to evaluate the safety, tolerability, pharmacokinetics, and efficacy of a phage drug product for treating acute uncomplicated UTI caused by MDR E. coli. Scientists are also exploring ways to optimize phage therapy by enhancing their effectiveness. For example, Locus is developing phage therapeutics that utilize CRISPR-Cas3 technology.
These phages deliver CRISPR-Cas3 to their bacterial host, resulting in irreversible damage to bacterial DNA. This method of action enables more potent bacterial eradication compared to traditional phages. Conley emphasized that the ability to modify phages, including incorporating various non-Cas payloads, enhances their potential as a crucial tool in combating antimicrobial resistance (AMR).
According to Strathdee, the future of phage therapy lies in the hands of the upcoming generation of scientists. A growing community of young researchers is enthusiastic about the prospects of phage therapy. This passion, combined with collaboration, increased funding, and advancements in clinical trials, will play a vital role in bringing phage therapy into the spotlight. As the saying goes, "Where there's a will, there's a way."
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