Phage therapy
Phage therapy, viral phage therapy, or phagotherapy is the therapeutic use of bacteriophages for the treatment of pathogenic bacterial infections. This therapeutic approach emerged at the beginning of the 20th century but was progressively replaced by the use of antibiotics in most parts of the world after the Second World War. Bacteriophages, known as phages, are a form of virus that attach to bacterial cells and inject their genome into the cell. The bacteria's production of the viral genome interferes with its ability to function, halting the bacterial infection. The bacterial cell causing the infection is unable to reproduce and instead produces additional phages. Phages are very selective in the strains of bacteria they are effective against.
Advantages include reduced side effects and reduced risk of the bacterium developing resistance, since bacteriophages are much more specific than antibiotics. They are typically harmless not only to the host organism but also to other beneficial bacteria, such as the gut microbiota, reducing the chances of opportunistic infections. They have a high therapeutic index; that is, phage therapy would be expected to give rise to few side effects, even at higher-than-therapeutic levels. Because phages replicate in vivo, a smaller effective dose can be used.
Disadvantages include the difficulty of finding an effective phage for a particular infection; a phage will kill a bacterium only if it matches the specific strain. However, virulent phages can be isolated much more easily than other compounds and natural products. Consequently, phage mixtures are sometimes used to improve the chances of success. Alternatively, samples taken from recovering patients sometimes contain appropriate phages that can be grown to cure other patients infected with the same strain. Ongoing challenges include the need to increase phage collections from reference phage banks, the development of efficient phage screening methods for the fast identification of the therapeutic phage, the establishment of efficient phage therapy strategies to tackle infectious biofilms, the validation of feasible phage production protocols that assure quality and safety of phage preparations, and the guarantee of stability of phage preparations during manufacturing, storage, and transport.
Phages tend to be more successful than antibiotics where there is a biofilm covered by a polysaccharide layer, which antibiotics typically cannot penetrate. Phage therapy can disperse the biofilm generated by antibiotic-resistant bacteria. However, the interactions between phages and biofilms can be complex, with phages developing symbiotic as well as predatory relationships with biofilms.
Phages are currently being used therapeutically to treat bacterial infections that do not respond to conventional antibiotics, particularly in Russia and Georgia. There is also a phage therapy unit in Wrocław, Poland, established in 2005, which continues several-decades-long research by the Institute of Immunology and Experimental Therapy of the Polish Academy of Sciences, the only such centre in a European Union country. Phages are the subject of renewed clinical attention in Western countries, such as the United States. In 2019, the United States Food and Drug Administration approved the first US clinical trial for intravenous phage therapy.
Phage therapy has many potential applications in human medicine as well as dentistry, veterinary science, and agriculture. If the target host of a phage therapy treatment is not an animal, the term "biocontrol" is usually employed, rather than "phage therapy".
History
The discovery of bacteriophages was reported by British bacteriologist Frederick Twort in 1915 and by French microbiologist Felix d'Hérelle in 1917. D'Hérelle said that the phages always appeared in the stools of Shigella dysentery patients shortly before they began to recover. He "quickly learned that bacteriophages are found wherever bacteria thrive: in sewers, in rivers that catch waste runoff from pipes, and in the stools of convalescent patients". Phage therapy was immediately recognized by many to be a key way forward for the eradication of pathogenic bacterial infections. A Georgian, George Eliava, was making similar discoveries. He travelled to the Pasteur Institute in Paris, where he met d'Hérelle, and in 1923, he founded the Institute of Bacteriology, which later became known as the George Eliava Institute, in Tbilisi, Georgia, devoted to the development of phage therapy. Phage therapy is used in Russia, Georgia and Poland, and was used prophylactically for a time in the Soviet army, most notably during the Second World War.In the Soviet Union, extensive research and development soon began in this field. In the United States during the 1940s, commercialization of phage therapy was undertaken by Eli Lilly and Company.
While knowledge was being accumulated regarding the biology of phages and how to use phage cocktails correctly, early uses of phage therapy were often unreliable. Since the early 20th century, research into the development of viable therapeutic antibiotics had also been underway, and by 1942, the antibiotic penicillin G had been successfully purified and saw use during the Second World War. The drug proved to be extraordinarily effective in the treatment of injured Allied soldiers whose wounds had become infected. By 1944, large-scale production of penicillin had been made possible, and in 1945, it became publicly available in pharmacies. Due to the drug's success, it was marketed widely in the US and Europe, leading Western scientists to mostly lose interest in further use and study of phage therapy for some time.
Isolated from Western advances in antibiotic production in the 1940s, Soviet scientists continued to develop already successful phage therapy to treat the wounds of soldiers in field hospitals. During World War II, the Soviet Union used bacteriophages to treat soldiers infected with various bacterial diseases, such as dysentery and gangrene. Soviet researchers continued to develop and to refine their treatments and to publish their research and results. However, due to the scientific barriers of the Cold War, this knowledge was not translated and did not proliferate across the world. A summary of these publications was published in English in 2009 in "A Literature Review of the Practical Application of Bacteriophage Research".
There is an extensive library and research center at the George Eliava Institute in Tbilisi, Georgia. Phage therapy is today a widespread form of treatment in that region.
As a result of the development of antibiotic resistance since the 1950s and an advancement of scientific knowledge, there has been renewed interest worldwide in the ability of phage therapy to eradicate bacterial infections and chronic polymicrobial biofilm.
Phages have been investigated as a potential means to eliminate pathogens like Campylobacter in raw food and Listeria in fresh food or to reduce food spoilage bacteria. In agricultural practice, phages have been used to fight pathogens like Campylobacter, Escherichia, and Salmonella in farm animals, Lactococcus and Vibrio pathogens in fish aquaculture, and Erwinia, Xanthomonas, and others in plants of agricultural importance. The oldest use is, however, in human medicine. Phages have been used against diarrheal diseases caused by E. coli, Shigella, or Vibrio and against wound infections caused by facultative pathogens of the skin like staphylococci and streptococci. Recently, the phage therapy approach has been applied to systemic and even intracellular infections, and non-replicating phage and isolated phage enzymes like lysins have been added to the antimicrobial arsenal. However, actual proof for the efficacy of these phage approaches in the field or the hospital is not available.
Some of the interest in the West can be traced back to 1994, when James Soothill demonstrated that the use of phages could improve the success of skin grafts by reducing the underlying Pseudomonas aeruginosa infection. Recent studies have provided additional support for these findings in the model system.
Although not "phage therapy" in the original sense, the use of phages as delivery mechanisms for traditional antibiotics constitutes another possible therapeutic use. The use of phages to deliver antitumor agents has also been described in preliminary in vitro experiments for cells in tissue culture.
In June 2015, the European Medicines Agency hosted a one-day workshop on the therapeutic use of bacteriophages, and in July 2015, the US National Institutes of Health hosted a two-day workshop titled "Bacteriophage Therapy: An Alternative Strategy to Combat Drug Resistance".
In January 2016, phages were used successfully at Yale University by Benjamin Chan to treat a chronic Pseudomonas aeruginosa infection in ophthalmologist Ali Asghar Khodadoust. This successful treatment of a life-threatening infection sparked a resurgence of interest in phage therapy in the United States.
In 2017, a pair of genetically engineered phages along with one naturally occurring each from among those catalogued by SEA-PHAGES at the Howard Hughes Medical Institute by Graham Hatfull and colleagues, was used by microbiologist James Soothill at Great Ormond Street Hospital for Children in London to treat an antibiotic-resistant bacterial infection in a young woman with cystic fibrosis.
In 2022, two mycobacteriophages were administered intravenously twice daily to a young man with treatment-refractory Mycobacterium abscessus pulmonary infection and severe cystic fibrosis lung disease. Airway cultures for M. abscessus became negative after approximately 100 days of combined phage and antibiotic treatment, and a variety of biomarkers confirmed the therapeutic response. The individual received a bilateral lung transplant after 379 days of treatment, and cultures from the explanted lung tissue confirmed eradication of the bacteria. In a second case, successful treatment of disseminated cutaneous Mycobacterium chelonae was reported with a single phage administered intravenously twice daily in conjunction with antibiotic and surgical management.