Phage Therapy: Exploring the Future of Infection Treatment

Globally, every year, about 7.7 million deaths occur due to bacterial infections with 750,000 deaths being attributed to antibiotic resistance.¹ With the rise in antibiotic resistance and failure of traditional antibiotics, interest in the practice of phage therapy in multidrug resistant organisms has increased as an alternative to treat bacterial infections.

Phages are naturally occurring or genetically engineered viruses that are incapable of reproducing independently and are ultimately dependent on a bacterial host for survival. Unlike antibiotics, phages are highly specific and have the capability of targeting harmful bacteria without affecting the body’s microflora. There are 2 types of phages: lytic and lysogenic.

An illustration of a group of phages or bacteriophages infecting bacteria. Image Credit: © Matthieu - stock.adobe.com

Phage therapy uses lytic bacteriophages that bind to specific receptors on the bacterial cell surface. The lytic bacteriophages inject their genetic material into the host cell and lyses the host cell, killing the bacteria.² On the other hand, lysogenic phages integrate their genome into the host cell and may eventually lyse the cell. Because of this delayed response, lysogenic phages can contribute to the spread of antimicrobial resistance. For this reason, only lytic phages are studied and used as part of phage therapy treatment.

The History of Phage Therapy

In 1915 and 1917, Frederick William Twort, a British microbiologist, and Felix d’Herelle, a French-Canadian microbiologist, independently discovered bacteriophages.In 1922, bacteriolysant bacteriophages were first used by Felix d’Herelle to treat dysentery in 12 children in Paris, but no beneficial effect was observed.³ In contrast, a 1925 placebo-controlled study by Spence et al of 31 patients with dysentery in the United States showed a reduced mortality rate with bacteriophage therapy (10.5% vs 41.7%; P value not provided) and decreased average time of recovery (5.8 days vs 12.8 days; P value not provided).³ This research stimulated excitement around the potential use of phage therapy. However, much of the research overall was being conducted by the Soviet Union and political differences led to avoidance in the US.

Antibiotics were discovered and became available shortly thereafter; due to their convenience, broad spectrum utility, and fewer scientific controversies, antibiotics quickly became the standard of care for bacterial infections in the Western Hemisphere.³ The outbreak of World War II contributed to a stall in research funding and time for phage therapy, which was not considered a priority. After the war, the pharmaceutical manufacturers focused research and development efforts on antibiotics which were effective, easy to administer, and profitable. While phage therapy continued to be used at times in Eastern European countries, their use essentially ceased by the 1970s.⁴ The use of antibiotics dominated bacterial infection treatment for the remainder of the 20th century. Unfortunately, broad, and sometimes over, use of antibiotics led to the development of bacterial resistance to most of the antibiotics currently available, raising concerns in the medical community about how to manage patients infected with resistant pathogens.

It was out of a need to find a solution that phage therapy resurfaced at the end of the 20th century as a potential therapeutic option. In 2015, physician Tom Patterson, MD, developed an infection from multidrug resistant Acinetobacter baumannii within an abdomen cyst while on vacation in Egypt.⁵ Over the next 9 months, he experienced 7 instances of septic shock and multiple complications. With no antibiotics possessing coverage against the particular infecting pathogen available, it was unsure if he would survive. His wife, an epidemiologist, came across the concept of phages in the medical literature and tirelessly championed the hunt for phages as a last option for her husband. Phages to match his organism were isolated from a variety of sources including sewage, barnyard waste, and even the bilges of ships. In 2016, he became the first person in the US to receive intravenous phage therapy for a systemic multidrug resistant infection, treatment that was only able to be administered after compassionate use approval was obtained by the FDA. Within 3 days of receiving treatment, he awoke from a coma.⁵

Understanding the Pharmaceutical Properties of Phages

Phages are viruses that are made of tightly packed immunogenic DNA or RNA surrounded by a protein coat.⁶

They naturally kill bacteria by lysing bacterial cells or inserting their genetic material into the bacteria to be integrated into the bacterial genome.⁶ Antibiotics and phage therapy both aim to eliminate bacteria, but they do so through different processes. When bacteria are exposed to phage therapy, the bacteria evolve to develop resistance to the phages, causing them to lose their resistance to antibiotics.⁷ Through this mechanism, bacteria become more susceptible to antibiotics, leading to a renewed effectiveness of older antibiotics.

Phages are highly specific for their target bacteria.⁸ Although individual phages are highly specific, there are over a nonillion (10³¹) distinct naturally occurring phages in the world, therefore every bacterium has multiple phages to which it is vulnerable.⁹ If a bacterial strain develops resistance to a phage, there is most likely another phage with the potential to target that bacterial strain. Phages can be put into “phage cocktails” to target multiple strains or pathogens simultaneously and can be tailored to individual patients, thus enhancing their effectiveness.⁸ In addition to this, phages have the ability to self-replicate and multiply over time, which may further increase their effectiveness.⁸ This means that the dose of the phages administered does not correlate with the dose that the patient will ultimately receive, but points toward less frequent administration to reach therapeutic effect with some only requiring a single dose. Unfortunately, the pharmacokinetics and pharmacodynamics of phages are quite complex and there is little understanding about the future of dosing phage therapy, as many cases lack generalizability.⁸

Phages have many different qualities that make therapy unique. One quality is that they distribute into many different organs with the highest accumulation being seen in the spleen and liver due to their role in filtering foreign particles.⁸ Phages can be dispersed by many different delivery methods including intravenous infusions, oral supplements, intranasal solutions, topical solutions, intramuscular, subcutaneous and intraperitoneal injections, and inhalations, but the FDA has not yet approved any of these products for human clinical use.^6,8 The majority of clinical trials are studying phages that are administered intravenously. Notably, the variety of administration routes will make phage therapy attractive for different patient populations as literature continues to grow in this topic. It also provides options for a variety of situations as the bioavailability may differ between delivery systems due to target sites, phage properties, and presence of host factors.

Phages are highly unstable due to internal and external factors including capsid size, tail length, high temperatures, acidity, or alkalinity. These factors cause phages to rely on their delivery system to encapsulate and protect the phage properties upon arrival at the target site.¹⁰ It is also understood that phages are distributed bidirectionally.⁸ Once phages are introduced to the host, they move toward the infection site and outward to infect bacteria in nearby areas allowing for better elimination of bacteria. Another distinct component that sets phage therapy apart is that phages do not undergo traditional metabolism; they either propagate or are inactivated by natural host immunity. Inactivation of phages occurs through many mechanisms such as macrophage and antibody attack to foreign invasion or by environmental factors which include low pH found in the stomach. It is important to note that this environmental inactivation may be reversed upon increasing the pH level.⁸ Once phages are inactivated, they must be cleared hepatically as they are too large to be cleared renally and are cleared by the reticuloendothelial system in the spleen.¹¹ Clearance rate depends on many patient-specific factors including infection type and site, renal function, age, and concurrent disease states.⁸

Due to their high specificity, phages have shown to be generally well-tolerated, but some transient adverse events consisting of mild inflammatory reactions, fever and chills, nausea, flushing, inflammation, hypotension, and gastrointestinal distress have been reported.¹² Phages are composed of mostly nucleic acids and proteins reflecting a nontoxic profile; however, they can interact with the immune system and cause harmful immune responses. Additionally, when the bacteria are lysed by the lytic bacteriophages, the bacteria may release endotoxins into the bloodstream triggering a sudden inflammatory response which can lead to serious conditions such as septic shock.¹³ However, the safety profile of phage therapy remains largely unknown due to its limited role in clinical practice and the relatively small number of controlled trials conducted to date.

Current Uses and Research of Phage Therapy

Phage therapy is currently used as compassionate therapy or expanded access, which is defined as treatment of a medical condition outside of clinical trials when there is no satisfactory or comparable alternative.¹⁴ The FDA has created initiatives such as the Adaptive Phage Therapeutics PhageBank, which houses information regarding these bacteriophages.¹⁵ The bank serves to match phages with the isolated bacterial strain for the patient to better target the causative organism. In the US, eligibility for bacteriophage therapy must require failed normally prescribed antibiotic treatments for the current bacterial infection. If a physician wants to pursue compassionate use of phage therapy for a patient, the physician must contact the Phage Directory at the Center for Innovative Phage Applications and Therapeutics in San Diego, a center which opened in 2018 and has had provided effective treatments using phage therapy.¹⁶ Another pathway for phage therapy is through clinical trial applications, but access may be limited by study inclusion and exclusion criteria.

Overall, information and data on phage therapy are limited. A 2021 case report described the first successful use of phage therapy in a 12-year-old child with cystic fibrosis with pandrug-resistant Achromobacter xylosoxidans.¹⁷ This was the first report of decolonization by phage therapy with this particular bacteria species after lung transplantation. A 2020 case report illustrated effective treatment of a prosthetic knee infection caused by Klebsiella pneumoniae using 40 doses of phage therapy in combination with minocycline.¹⁸ The patient experienced a reduction of local symptoms and signs of infection within 22 hours of phage administration and full recovery by week 8.

It is important to note that phage therapy has not been universally successful. A case report published in 2023 discussed unsuccessful treatment with phage therapy in a patient with Pseudomonas aeruginosa from a prosthetic vascular graft infection.¹⁹ This case included treatment with a phage cocktail in addition to ceftazidime-avibactam. It is believed that this therapy failed due to infection recurrence caused by an antibiotic susceptible isolate belonging to the same lineage. Incidence of recurrence should be investigated further to determine efficacy and develop future guidelines. A 2009 study (n=24) of chronic otitis caused by antibiotic resistant Pseudomonas aeruginosa involving a 6-phage preparation showed a reduction in inflammation, ulceration, discharge type, discharge quantity, and odor at day 42, but only 3 of the 12 patients who received phage therapy were cured.²⁰ Another 2009 placebo-controlled study (n=42) of a topical phage cocktail targeting Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa occurring in venous leg ulcers showed no difference compared to saline on rate and frequency of ulcer healing.²⁰

However, it is worth noting that the phages were not tested for infectivity on the bacteria that were actually causing the ulcers, which would be comparable to studying an antibiotic without knowing if the patient was infected with bacteria for which the drug provides coverage. A 2013 multicenter phase 1/2 study in France and Belgium involving burn patients with wounds infected by Pseudomonas aeruginosa (n=27) treated with a cocktail of 12 lytic phages or 1% sulfadiazine silver emulsion cream showed that, despite a reduced bacterial burden with phage therapy, wound healing was slower than standard care with the cream.²⁰ In this study, a significant drop of phage titer after good manufacturing practices (GMP) resulting in participants receiving a subtherapeutic concentration of phages than originally estimated, which complicates interpretation of the study’s results.

Currently, there are 3 active, non-recruiting clinical trials evaluating phage therapy. A phase 1/2 trial in Canada is evaluating the treatment of drug-resistant urinary tract infections with a 3-phage cocktail.²¹ A trial conducted in Uzbekistan is studying treatment of tonsillitis with nebulized bacteriophages.²² The third is a phase 1b/2a trial being conducted in 28 locations across the US, Spain, Netherlands, Israel, and Czechia to evaluate nebulized bacteriophage treatment in outpatient adult cystic fibrosis patients with chronic Pseudomonas aeruginosa infection.²³ Unfortunately all 3 studies involve a niche patient population and are still in the early phases of clinical trials; therefore, a full understanding of the safety and efficacy of phage therapy in the broader population will remain unclear. Still, the studies will provide some much-needed modern evidence based data beyond case reports and may serve to advance further research and development of these unique therapies.

Challenges

Despite the potential advantages of phage therapy in treatment of complicated infectious disease, there remain a variety of challenges to development. Pharmacokinetics (PK) of phage therapy is more complicated than antibiotics which are fixed composition small molecules.¹¹ Though PK parameters could be determined in a laboratory setting, inter-individual (both human and bacteria) differences, inter-phage variables, and impact of immune system on PK may make it difficult to clearly determine these parameters in the same way that are traditionally understood.¹¹ Ideal dosing and route of administration has not been determined, and the order of phage administration, and the consideration that some phages are synergistic while others are antagonistic, could impact treatment outcomes.¹¹ For broad production, phages would need to be manufactured under GMP, but no clear guidelines currently exist for phage production.²⁰

An independent group of phage researchers have proposed safety and quality requirements, one of which is to avoid phages encoding for lysogeny, virulence factors, or antibiotic resistance. Unfortunately, this would limit development of phage therapy for fastidious bacteria, such as Clostridioides difficile, where no strictly virulent phages have been discovered to date.²⁰ Another challenge is the need to avoid impurities such as endotoxins in phage production; while multiple purification methods have been created, none have yet produced optimal results.²⁰ Other challenges currently impacting phage development include product stability and occurrence of spontaneous mutations in phages stored over long periods or presenting during manufacturing.²⁰ Additionally, it appears that phage therapy may need to be individualized to a specific patient which is complicated by current laws and regulation directing medication production.²⁰ In case reports and studies available, phage therapy has overall been safe, but theoretical concerns of immunologic complications based on phage mechanism have been raised and must be addressed.^11,20

Conclusion

Although phage therapy has an extensive history, its resurgence in recent years due to concerns of antibiotic resistance signifies its potential to become a vital tool in modern medicine. Current research, clinical trials and case reports demonstrate its potential efficacy in treating a range of resistant infections. However, challenges remain in the areas of public education, production, regulatory approval, and commercialization. With continued research and refinement, phage therapy may play a critical role in combating the global threat of antibiotic resistance.

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