Phage therapy#Plants

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File:Félix d'Hérelle.jpg, discoverer of phage therapy]]

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The discovery of bacteriophages was reported by British bacteriologist Frederick Twort in 1915{{cite journal |doi=10.1016/S0140-6736(01)20383-3 |title=An investigation on the nature of ultra-microscopic viruses |journal=The Lancet |volume=186 |issue=4814 |pages=1241–1243 |year=1915 |vauthors=Twort FW |url=https://babel.hathitrust.org/cgi/pt?id=iau.31858021447929;view=1up;seq=513 |access-date=1 May 2018 |archive-date=10 December 2019 |archive-url=https://web.archive.org/web/20191210130115/https://babel.hathitrust.org/cgi/pt?id=iau.31858021447929;view=1up;seq=513 |url-status=live }} and by French microbiologist Felix d'Hérelle in 1917.{{cite journal|vauthors=D'Herelle F|title=Sur un microbe invisible antagoniste des bacilles dysenteriques|journal=Comptes Rendus|date=1917|volume=165|pages=373–375|url=https://www.biodiversitylibrary.org/item/31787#page/379/mode/1up|trans-title=An invisible microbe that is antagonistic to the dysentery bacillus|language=fr|access-date=1 May 2018|archive-date=11 October 2018|archive-url=https://web.archive.org/web/20181011212632/https://www.biodiversitylibrary.org/item/31787#page/379/mode/1up|url-status=live}} 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.{{cite journal | vauthors = Chanishvili N, Myelnikov D, Blauvelt TK | title = Professor Giorgi Eliava and the Eliava Institute of Bacteriophage | journal = Phage | volume = 3 | issue = 2 | pages = 71–80 | date = June 2022 | pmid = 36157286 | pmc = 9436386 | doi = 10.1089/phage.2022.0016 }} Phage therapy is used in Russia,{{cite news |title=State Register of Medicines |url=https://grls.rosminzdrav.ru/GRLS.aspx?RegNumber=&MnnR=%D0%B1%D0%B0%D0%BA%D1%82%D0%B5%D1%80%D0%B8%D0%BE%D1%84%D0%B0%D0%B3&lf=&TradeNmR=&OwnerName=&MnfOrg=&MnfOrgCountry=&isfs=0®type=1%2c6&pageSize=10&order=Registered&orderType=desc&pageNum=1 |website=grls.rosminzdrav.ru |access-date=12 September 2023 |archive-date=15 May 2024 |archive-url=https://web.archive.org/web/20240515012758/https://grls.rosminzdrav.ru/GRLS.aspx?RegNumber=&MnnR=%D0%B1%D0%B0%D0%BA%D1%82%D0%B5%D1%80%D0%B8%D0%BE%D1%84%D0%B0%D0%B3&lf=&TradeNmR=&OwnerName=&MnfOrg=&MnfOrgCountry=&isfs=0®type=1%2c6&pageSize=10&order=Registered&orderType=desc&pageNum=1 |url-status=live }} 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.{{Cite web |title=Phage 101 – Bacteriophage Therapy |url=https://health.ucsd.edu/news/topics/phage-therapy/Pages/Phage-101.aspx |access-date=15 March 2022 |website=UC Health – UC San Diego |archive-date=23 August 2023 |archive-url=https://web.archive.org/web/20230823124158/https://health.ucsd.edu/news/ |url-status=live }}

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.{{cite journal | vauthors = Summers WC | title = The strange history of phage therapy | journal = Bacteriophage | volume = 2 | issue = 2 | pages = 130–133 | date = April 2012 | pmid = 23050223 | pmc = 3442826 | doi = 10.4161/bact.20757 }} 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 (including in industrial situations).

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.{{cite journal | vauthors = Balogh B, Jones JB, Iriarte FB, Momol MT | title = Phage therapy for plant disease control | journal = Current Pharmaceutical Biotechnology | volume = 11 | issue = 1 | pages = 48–57 | date = January 2010 | pmid = 20214607 | doi = 10.2174/138920110790725302 | publisher = Bentham Science Publishers | s2cid = 20820594 }}{{cite journal | vauthors = Wang N, Pierson EA, Setubal JC, Xu J, Levy JG, Zhang Y, Li J, Rangel LT, Martins J | display-authors = 6 | title = The Candidatus Liberibacter-Host Interface: Insights into Pathogenesis Mechanisms and Disease Control | journal = Annual Review of Phytopathology | volume = 55 | issue = 1 | pages = 451–482 | date = August 2017 | pmid = 28637377 | doi = 10.1146/annurev-phyto-080516-035513 | publisher = Annual Reviews | s2cid = 207653521 }}{{cite journal | vauthors = Varani AM, Monteiro-Vitorello CB, Nakaya HI, Van Sluys MA | title = The role of prophage in plant-pathogenic bacteria | journal = Annual Review of Phytopathology | volume = 51 | issue = 1 | pages = 429–451 | date = 4 August 2013 | pmid = 23725471 | doi = 10.1146/annurev-phyto-081211-173010 | publisher = Annual Reviews | s2cid = 207644125 }} 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 (in an animal model) 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,{{cite web|url=http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/events/2015/05/event_detail_001155.jsp&mid=WC0b01ac058004d5c3|title=European Medicines Agency – News and Events – Workshop on the therapeutic use of bacteriophages|website=www.ema.europa.eu|date=17 September 2018|access-date=20 August 2015|archive-date=23 August 2023|archive-url=https://web.archive.org/web/20230823124206/https://www.ema.europa.eu/en/events/workshop-therapeutic-use-bacteriophages|url-status=dead}} 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".{{cite web|url=https://respond.niaid.nih.gov/conferences/bacteriophage/Pages/Agenda.aspx|title=Bacteriophage Therapy: An Alternative Strategy to Combat Drug Resistance|website=respond.niaid.nih.gov|access-date=20 August 2015|archive-url=https://web.archive.org/web/20160701031513/https://respond.niaid.nih.gov/conferences/bacteriophage/Pages/Agenda.aspx|archive-date=1 July 2016|url-status=dead}}

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.{{cite news |vauthors=Zimmer C |url=https://www.statnews.com/2016/12/07/virus-bacteria-phage-therapy/ |title=A virus, fished out of a lake, may have saved a man's life – and advanced science |work=Stat News |date=7 December 2016 |access-date=30 January 2021 |archive-date=8 December 2016 |archive-url=https://web.archive.org/web/20161208121433/https://www.statnews.com/2016/12/07/virus-bacteria-phage-therapy/ |url-status=live }} This successful treatment of a life-threatening infection sparked a resurgence of interest in phage therapy in the United States.{{citation needed|date=February 2023}}

In 2017, a pair of genetically engineered phages along with one naturally occurring (so-called "phage Muddy") each from among those catalogued by SEA-PHAGES (Science Education Alliance-Phage Hunters Advancing Genomics and Evolutionary Science) 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 (Mycobacterium abscessus) infection in a young woman with cystic fibrosis.{{Cite news |vauthors=Stein R |url=https://www.npr.org/sections/health-shots/2019/05/08/719650709/genetically-modified-viruses-help-save-a-patient-with-a-superbug-infection |title=Genetically Modified Viruses Help Save a Patient With a 'Superbug' Infection |website=NPR.org |access-date=9 May 2019 |archive-date=23 August 2023 |archive-url=https://web.archive.org/web/20230823124200/https://www.npr.org/sections/health-shots/2019/05/08/719650709/genetically-modified-viruses-help-save-a-patient-with-a-superbug-infection |url-status=live }}{{Cite news |url=https://www.bbc.com/news/health-48199915 |title=Phage therapy: 'Viral cocktail saved my daughter's life' |date=8 May 2019 |work=BBC News |vauthors=Gallagher J |access-date=29 December 2019 |archive-date=23 August 2023 |archive-url=https://web.archive.org/web/20230823124209/https://www.bbc.com/news/health-48199915 |url-status=live }}{{Cite web |vauthors=Srisuknimit V |url=https://www.genengnews.com/insights/phage-therapy-win-mycobacterium-infection-halted/ |title=Phage Therapy Win: Mycobacterium Infection Halted |work=Genetic Engineering & Biotechnology News |date=8 May 2019 |access-date=9 May 2019 |archive-date=23 August 2023 |archive-url=https://web.archive.org/web/20230823124240/https://www.genengnews.com/insights/phage-therapy-win-mycobacterium-infection-halted/ |url-status=live }}

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.{{cite journal | vauthors = Nick JA, Dedrick RM, Gray AL, Vladar EK, Smith BE, Freeman KG, Malcolm KC, Epperson LE, Hasan NA, Hendrix J, Callahan K, Walton K, Vestal B, Wheeler E, Rysavy NM, Poch K, Caceres S, Lovell VK, Hisert KB, de Moura VC, Chatterjee D, De P, Weakly N, Martiniano SL, Lynch DA, Daley CL, Strong M, Jia F, Hatfull GF, Davidson RM | display-authors = 6 | title = Host and pathogen response to bacteriophage engineered against Mycobacterium abscessus lung infection | language = English | journal = Cell | date = May 2022 | volume = 185 | issue = 11 | pages = 1860–1874.e12 | pmid = 35568033 | doi = 10.1016/j.cell.2022.04.024 | pmc = 9840467 | s2cid = 248755782 }} 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.{{cite journal | vauthors = Little JS, Dedrick RM, Freeman KG, Cristinziano M, Smith BE, Benson CA, Jhaveri TA, Baden LR, Solomon DA, Hatfull GF | display-authors = 6 | title = Bacteriophage treatment of disseminated cutaneous Mycobacterium chelonae infection | journal = Nature Communications | volume = 13 | issue = 1 | pages = 2313 | date = May 2022 | pmid = 35504908 | pmc = 9064978 | doi = 10.1038/s41467-022-29689-4 | bibcode = 2022NatCo..13.2313L }}

File:Phage Therapy.svg

Bacteriophage treatment offers a possible alternative to conventional antibiotic treatments for bacterial infection. It is conceivable that, although bacteria can develop resistance to phages, the resistance might be easier to overcome than resistance to antibiotics.{{cite journal | vauthors = Carlton RM | title = Phage therapy: past history and future prospects | journal = Archivum Immunologiae et Therapiae Experimentalis | volume = 47 | issue = 5 | pages = 267–274 | date = 1999 | pmid = 10604231 | url = http://www.cienciaviva.eu/rede/oceanos/2desafio/visaogeral.pdf | archive-url = https://web.archive.org/web/20160327092032/http://www.cienciaviva.eu/rede/oceanos/2desafio/visaogeral.pdf | archive-date = 27 March 2016 }} Viruses, just like bacteria, can evolve resistance to different treatments.

Bacteriophages are very specific, targeting only one or a few strains of bacteria. Traditional antibiotics have a more wide-ranging effect, killing both harmful and useful bacteria, such as those facilitating food digestion.{{cite journal | vauthors = Zhang S, Chen DC | title = Facing a new challenge: the adverse effects of antibiotics on gut microbiota and host immunity | language = en-US | journal = Chinese Medical Journal | volume = 132 | issue = 10 | pages = 1135–1138 | date = May 2019 | pmid = 30973451 | pmc = 6511407 | doi = 10.1097/CM9.0000000000000245 }} The species and strain specificity of bacteriophages makes it unlikely that harmless or useful bacteria will be killed when fighting an infection.{{cite journal | vauthors = Choudhury TG, Maiti B, Venugopal MN, Karunasagar I | title = Influence of some environmental variables and addition of r-lysozyme on efficacy of Vibrio harveyi phage for therapy | journal = Journal of Biosciences | volume = 44 | issue = 1 | date = March 2019 | pmid = 30837359 | doi = 10.1007/s12038-018-9830-x | s2cid = 59524581 }}

A few research groups in the West are engineering a broader-spectrum phage and also a variety of forms of MRSA treatments, including impregnated wound dressings, preventative treatment for burn victims, and phage-impregnated sutures. Enzybiotics are a new development at Rockefeller University that create enzymes from phages. Purified recombinant phage enzymes can be used as separate antibacterial agents in their own right.

Phage therapy also has the potential to prevent or treat infectious diseases of corals. This could mitigate the global coral decline.{{cite journal | vauthors = Efrony R, Atad I, Rosenberg E | title = Phage therapy of coral white plague disease: properties of phage BA3 | journal = Current Microbiology | volume = 58 | issue = 2 | pages = 139–145 | date = February 2009 | pmid = 18923867 | doi = 10.1007/s00284-008-9290-x | s2cid = 1823011 }}

Phages for therapeutic use can be collected from environmental sources that likely contain high quantities of bacteria and bacteriophages, such as effluent outlets, sewage, or even soil. The samples are taken and applied to bacterial cultures that are to be targeted. If the bacteria die, the phages can be grown in liquid cultures.

Phages are "bacterium-specific", and therefore, it is necessary in many cases to take a swab from the patient and culture it prior to treatment. Occasionally, isolation of therapeutic phages can require a few months to complete, but clinics generally keep supplies of phage cocktails for the most common bacterial strains in a geographical area.{{citation needed|date=February 2023}}

Phage cocktails are commonly sold in pharmacies in Eastern European countries, such as Russia and Georgia.{{cite journal | vauthors = McCallin S, Alam Sarker S, Barretto C, Sultana S, Berger B, Huq S, Krause L, Bibiloni R, Schmitt B, Reuteler G, Brüssow H | display-authors = 6 | title = Safety analysis of a Russian phage cocktail: from metagenomic analysis to oral application in healthy human subjects | journal = Virology | volume = 443 | issue = 2 | pages = 187–196 | date = September 2013 | pmid = 23755967 | doi = 10.1016/j.virol.2013.05.022 | doi-access = free }}{{cite journal | vauthors = Abedon ST, Kuhl SJ, Blasdel BG, Kutter EM | title = Phage treatment of human infections | journal = Bacteriophage | volume = 1 | issue = 2 | pages = 66–85 | date = March 2011 | pmid = 22334863 | pmc = 3278644 | doi = 10.4161/bact.1.2.15845 }} The composition of bacteriophagic cocktails has been periodically modified to add phages effective against emerging pathogenic strains.{{cite journal | vauthors = Villarroel J, Larsen MV, Kilstrup M, Nielsen M | title = Metagenomic Analysis of Therapeutic PYO Phage Cocktails from 1997 to 2014 | journal = Viruses | volume = 9 | issue = 11 | pages = 328 | date = November 2017 | pmid = 29099783 | pmc = 5707535 | doi = 10.3390/v9110328 | doi-access = free }}

Phages in practice are applied orally, topically on infected wounds or spread onto surfaces, or during surgical procedures. Injection is rarely used, avoiding any risks of trace chemical contaminants that may be present from the bacteria amplification stage, and recognizing that the immune system naturally fights against viruses introduced into the bloodstream or lymphatic system.{{citation needed|date=February 2023}}

Reviews of phage therapy indicate that more clinical and microbiological research is needed to meet current standards.

{{update | section|date=February 2022}}

Funding for phage therapy research and clinical trials is generally insufficient and difficult to obtain, since it is a lengthy and complex process to patent bacteriophage products. Due to the specificity of phages, phage therapy would be most effective as a cocktail injection, a modality generally rejected by the US Food and Drug Administration (FDA). Therefore, researchers and observers have predicted that if phage therapy is to gain traction, the FDA must change its regulatory stance on combination drug cocktails. Public awareness and education about phage therapy are generally limited to scientific or independent research rather than mainstream media.

In 2007, phase-1 and 2 clinical trials were completed at the Royal National Throat, Nose and Ear Hospital, London, for Pseudomonas aeruginosa infections (otitis).

Phase-1 clinical trials were conducted at the Southwest Regional Wound Care Center of Lubbock, Texas, for a cocktail of phages against P. aeruginosa, Staphylococcus aureus, and Escherichia coli, developed by Intralytix. {{vanchor|PhagoBurn}}, a phase-1 and 2 trial of phage therapy against P. aeruginosa wound infection in France and Belgium in 2015–17, was terminated early due to lack of effectiveness.{{cite journal | vauthors = Jault P, Leclerc T, Jennes S, Pirnay JP, Que YA, Resch G, Rousseau AF, Ravat F, Carsin H, Le Floch R, Schaal JV, Soler C, Fevre C, Arnaud I, Bretaudeau L, Gabard J | display-authors = 6 | title = Efficacy and tolerability of a cocktail of bacteriophages to treat burn wounds infected by Pseudomonas aeruginosa (PhagoBurn): a randomised, controlled, double-blind phase 1/2 trial | journal = The Lancet. Infectious Diseases | volume = 19 | issue = 1 | pages = 35–45 | date = January 2019 | pmid = 30292481 | doi = 10.1016/S1473-3099(18)30482-1 | s2cid = 52930681 }}

Locus Biosciences has created a cocktail of three CRISPR-modified phages. A 2019 study examined its effectiveness against E. coli in the urinary tract,{{cite news |vauthors=Stein R |title=Scientists Modify Viruses with CRISPR to Create New Weapon Against Superbugs |url=https://www.npr.org/sections/health-shots/2019/05/22/723582726/scientists-modify-viruses-with-crispr-to-create-new-weapon-against-superbugs |access-date=28 May 2019 |agency=NPR |date=22 May 2019 |archive-date=23 August 2023 |archive-url=https://web.archive.org/web/20230823124207/https://www.npr.org/sections/health-shots/2019/05/22/723582726/scientists-modify-viruses-with-crispr-to-create-new-weapon-against-superbugs |url-status=live }} and a phase-1 trial was completed shortly before March 2021.{{Cite news |vauthors=Eanes Z |date=9 March 2021 |title=Locus using gene-editing technology to get ahead of drug-resistant bacteria |pages=B4 |work=The Herald-Sun |url=https://www.newspapers.com/clip/107926055/locus/ |access-date=19 August 2022 |via=Newspapers.com |archive-date=23 August 2023 |archive-url=https://web.archive.org/web/20230823124213/https://www.newspapers.com/article/107926055/locus/ |url-status=live }} In February 2019, the FDA approved the first clinical trial of intravenously administered phage therapy in the United States.{{cite journal | vauthors = Voelker R | title = FDA Approves Bacteriophage Trial | journal = JAMA | volume = 321 | issue = 7 | pages = 638 | date = February 2019 | pmid = 30778586 | doi = 10.1001/jama.2019.0510 | s2cid = 73464136 }}

In July 2020, the FDA approved the first clinical trial of nebulized phage therapy in the United States.{{ClinicalTrialsGov|NCT04684641|CYstic Fibrosis bacterioPHage Study at Yale (CYPHY): A Single-site, Randomized, Double-blind, Placebo-controlled Study of Bacteriophage Therapy YPT-01 for Pseudomonas Aeruginosa Infections in Adults With Cystic Fibrosis }} This double-blind, placebo-controlled study at Yale University will be focused on treating P. aeruginosa infections in patients with cystic fibrosis.{{medical citation needed|date=August 2024}}

In February 2020, the FDA approved a clinical trial to evaluate bacteriophage therapy in patients with urinary tract infections.{{ClinicalTrialsGov|NCT04287478|A Phase I/II Study of Bacteriophage Therapy to Evaluate Safety, Tolerability, and Efficacy of Targeted "Personalized" Bacteriophage Treatments in Patients With Bacterial Infection of the Urinary Tract }} The study started in December 2020 and aims to identify ideal bacteriophage treatment regimens based on improvements in disease control rates.

In February 2021, the FDA approved a clinical trial to evaluate bacteriophage therapy in patients with chronic prosthetic joint infections (PJI).{{ClinicalTrialsGov|NCT04787250|Randomized Open Label, Parallel Group, Controlled Study to Evaluate the Safety and Surgery Sparing Effect of Phage Therapy with Antibiotics for Patients with Prosthetic Joint Infections Who Are Candidates for Two Stage Exchange Arthroplasty }} The study was to begin in October 2022 and be conducted by Adaptive Phage Therapeutics, in collaboration with the Mayo Clinic.{{cite journal | vauthors = Hazra M, Dubey RC, Hazra S | title = Phage Therapy: The Ultimate Alternative Against Antibiotic Resistance (ABR) – Challenges, Advantages, Opportunities and the Pivotal Role of DNA-binding Proteins in Steering Modern Strategies Through Lytic-Lysogenic Control | journal = Science and Culture | volume = 90 | issue = 11–12 | pages = 490–506 | date = November 2024 | doi = 10.36094/sc.v89.2024.Phage_Therapy_the_Ultimate_Alternative_Against.Hazra.490 | doi-access = free }}

If administered as pills, phages can be freeze-dried; this procedure does not reduce efficiency. Temperature stability up to 55 °C and shelf lives of 14 months have been shown for some types of phages in pill form.

File:Liquid bacteriophage 20ml.jpg

Application in liquid form is possible, stored preferably in refrigerated vials. Oral administration works better when an antacid is included, as this increases the number of phages surviving passage through the stomach. Topical administration often involves application to gauzes that are laid on the area to be treated. Liquid bacteriophages are also utilized for local applications, such as wound dressings and topical treatments, as well as external administration, including sprays and rinses.

The July 2020 application for FDA approval for the first clinical trial of nebulized phage therapy in the United States does not specify a particular type of nebulizer, such as a compressor or ultrasound type.{{cite web | url=https://cysticfibrosisnewstoday.com/news/fda-clears-phase-1b-2a-cf-clinical-trial-ap-pa02-phage-therapy-against-pseudomonas-aeruginosa-infections/ | title=FDA Clears AP-PA02 Phage Therapy Trial for CF P. Aeruginosa Infections | date=20 October 2020 | access-date=8 August 2024 | archive-date=8 August 2024 | archive-url=https://web.archive.org/web/20240808200111/https://cysticfibrosisnewstoday.com/news/fda-clears-phase-1b-2a-cf-clinical-trial-ap-pa02-phage-therapy-against-pseudomonas-aeruginosa-infections/ | url-status=live }}{{cite web | url=https://www.fda.gov/regulatory-information/search-fda-guidance-documents/reviewer-guidance-nebulizers-metered-dose-inhalers-spacers-and-actuators | title=Reviewer Guidance for Nebulizers, Metered Dose Inhalers, Spacers and Actuators | website=Food and Drug Administration | date=17 March 2020 | access-date=8 August 2024 | archive-date=8 August 2024 | archive-url=https://web.archive.org/web/20240808195533/https://www.fda.gov/regulatory-information/search-fda-guidance-documents/reviewer-guidance-nebulizers-metered-dose-inhalers-spacers-and-actuators | url-status=live }}{{cite web|url=https://www.fda.gov/files/drugs/published/Regulatory-Perspectives-for-Device-Development-for-Inhalation-Combination-Products.pdf|archive-url=https://web.archive.org/web/20240808195533/https://www.fda.gov/files/drugs/published/Regulatory-Perspectives-for-Device-Development-for-Inhalation-Combination-Products.pdf |date=8 August 2024 |title=Regulatory Perspectives for Device Development for Inhalation Combination Products|publisher=FDA, Respiratory Devices Branch| vauthors = Lakhani D |archive-date=8 August 2024 }}{{cite journal | url=https://doi.org/10.1001/jama.2019.0510 | doi=10.1001/jama.2019.0510 | title=FDA Approves Bacteriophage Trial | date=2019 | journal=JAMA | volume=321 | issue=7 | page=638 | pmid=30778586 | vauthors = Voelker R | url-access=subscription }} Bacteriophages are studied as potential candidates for treating bacterial lung infections, especially those caused by multidrug-resistant (MDR) bacteria. In these studies, bacteriophage solutions are administered via nebulizers, mostly using the compressor type. The stability and viability of phages during nebulization are crucial for their therapeutic efficacy. Current studies focus on whether phages can remain viable and effective when delivered via nebulizers. The choice of nebulizer can impact the stability and delivery efficiency of phages. Compressor nebulizers are commonly used because they generate a fine mist that can reach the lower respiratory tract.{{cite journal | doi=10.3390/cells12162057 | doi-access=free | title=Stability Considerations for Bacteriophages in Liquid Formulations Designed for Nebulization | date=2023 | journal=Cells | volume=12 | issue=16 | page=2057 | pmid=37626867 | vauthors = Flint R, Laucirica DR, Chan H, Chang BJ, Stick SM, Kicic A | pmc=10453214 }}

In contrast to the compressor nebulizers, the ultrasound nebulizers can impact the viability of bacteriophages. The ultrasonic waves used to generate the aerosol can cause physical damage to the phages, potentially reducing their effectiveness. Preliminary research suggests the high-frequency vibrations and heat generated during the nebulization process can lead to a significant loss of phage activity. Consequently, one of the main challenges is ensuring that the phages remain undamaged during the nebulization process. Studies have shown that phages can be sensitive to the shear forces generated during nebulization. Still, with proper formulation and device selection, it is possible to maintain their viability, as the current research suggests.{{cite book | url=https://www.taylorfrancis.com/chapters/edit/10.1201/9781003269014-8/nebulizers-paul-terry-rajiv-dhand | doi=10.1201/9781003269014-8 | series=Nebulizers | title=Inhaled Delivery Systems for the Treatment of Asthma and COPD | date=2023 | pages=89–111 | isbn=978-1-003-26901-4 | vauthors = Terry PD, Dhand R | chapter=Nebulizers }}{{cite book | url=https://www.taylorfrancis.com/chapters/edit/10.1201/9781003182566-18/nebulizers-ariel-berlinski | doi=10.1201/9781003182566-18 | series=Nebulizers | title=Organ Specific Drug Delivery and Targeting to the Lungs | date=2022 | pages=431–452 | isbn=978-1-003-18256-6 | vauthors=Berlinski A | chapter=Nebulizers | access-date=8 August 2024 | archive-date=8 August 2024 | archive-url=https://web.archive.org/web/20240808200113/https://www.taylorfrancis.com/chapters/edit/10.1201/9781003182566-18/nebulizers-ariel-berlinski | url-status=live }}{{cite journal | url=https://doi.org/10.1016/0041-624X(90)90066-W | doi=10.1016/0041-624X(90)90066-W | title=Microbial content of aerosols produced from suspensions exposed to megahertz frequency ultrasound | date=1990 | journal=Ultrasonics | volume=28 | issue=6 | pages=415–421 | pmid=2238248 | vauthors = Grundy M, Coakley W, Clarke D | url-access=subscription }}

Phages were used successfully at Yale University by Benjamin Chan to treat a Pseudomonas infection in 2016. Intravenous phage drip therapy was successfully used to treat a patient with multidrug-resistant Acinetobacter baumannii in Thornton Hospital at UC San Diego in 2017.{{cite web|url=https://health.ucsd.edu/news/releases/Pages/2017-04-25-novel-phage-therapy-saves-patient-with-multidrug-resistant-bacterial-infection.aspx|title=Novel Phage Therapy Saves Patient with Multidrug-Resistant Bacterial Infection|publisher=UC San Diego Health|date=25 April 2017|access-date=16 March 2018|archive-date=10 October 2019|archive-url=https://web.archive.org/web/20191010235933/https://health.ucsd.edu/news/releases/pages/2017-04-25-novel-phage-therapy-saves-patient-with-multidrug-resistant-bacterial-infection.aspx|url-status=live}} Nebulized phage therapy has been used successfully to treat numerous patients with cystic fibrosis and multidrug-resistant bacteria at Yale University as part of their compassionate use program.{{cite news |vauthors=Ghorayshi A |title=This Scientist Used Live Viruses to Save a Woman's Life from a Superbug Infection |url=https://www.buzzfeednews.com/article/azeenghorayshi/phage-therapy-follow-this |work=Buzzfeed News |date=12 November 2018 |access-date=30 January 2021 |archive-date=23 August 2023 |archive-url=https://web.archive.org/web/20230823124212/https://www.buzzfeednews.com/article/azeenghorayshi/phage-therapy-follow-this |url-status=live }}{{cite news |author= |title=The 26-year-old who inhaled a virus to fight an antibiotic-resistant superbug |url=https://nypost.com/2019/02/26/the-26-year-old-who-inhaled-a-virus-to-fight-an-antibiotic-resistant-superbug/ |work=NY Post |date=26 February 2019 |access-date=30 January 2021}} In 2019, a Brownsville, Minnesota resident with a longstanding bacterial infection in his knee received a phage treatment at the Mayo Clinic that eliminated the need for amputation of his lower leg.{{cite web |title=He was going to lose his leg until doctors turned to cure older than dirt |url=https://www.oregonlive.com/health/2019/12/he-was-going-to-lose-his-leg-until-doctors-turned-to-cure-older-than-dirt.html |website=OregonLive.com |publisher=Minneapolis Star Tribune |access-date=28 December 2019 |date=28 December 2019 |archive-date=28 December 2019 |archive-url=https://web.archive.org/web/20191228220818/https://www.oregonlive.com/health/2019/12/he-was-going-to-lose-his-leg-until-doctors-turned-to-cure-older-than-dirt.html |url-status=live }} Individualised phage therapy was also successfully used by Robert T. Schooley and others to treat a case of multi-drug-resistant Acinetobacter baumannii in 2015.{{Cite web|url=https://thebulletin.org/2018/10/bacteriophages-a-promising-approach-to-fighting-antibiotic-resistant-bacteria/|title=Bacteriophages: a promising approach to fighting antibiotic-resistant bacteria|vauthors=Kahn L|date=9 October 2018|website=Bulletin of the Atomic Scientists|access-date=15 April 2019|archive-date=15 April 2019|archive-url=https://web.archive.org/web/20190415033223/https://thebulletin.org/2018/10/bacteriophages-a-promising-approach-to-fighting-antibiotic-resistant-bacteria/|url-status=live}}{{cite journal | vauthors = Schooley RT, Biswas B, Gill JJ, Hernandez-Morales A, Lancaster J, Lessor L, Barr JJ, Reed SL, Rohwer F, Benler S, Segall AM, Taplitz R, Smith DM, Kerr K, Kumaraswamy M, Nizet V, Lin L, McCauley MD, Strathdee SA, Benson CA, Pope RK, Leroux BM, Picel AC, Mateczun AJ, Cilwa KE, Regeimbal JM, Estrella LA, Wolfe DM, Henry MS, Quinones J, Salka S, Bishop-Lilly KA, Young R, Hamilton T | display-authors = 6 | title = Development and Use of Personalized Bacteriophage-Based Therapeutic Cocktails to Treat a Patient with a Disseminated Resistant Acinetobacter baumannii Infection | journal = Antimicrobial Agents and Chemotherapy | volume = 61 | issue = 10 | pages = e00954-17 | date = October 2017 | pmid = 28807909 | pmc = 5610518 | doi = 10.1128/AAC.00954-17 }} In 2022, an individually adjusted phage-antibiotic combination as an antimicrobial resistance treatment was demonstrated and described in detail.{{cite news |title=Phage therapies for superbug infections are being tested in Belgium |url=https://www.newscientist.com/article/2304997-phage-therapies-for-superbug-infections-are-being-tested-in-belgium/ |access-date=14 February 2022 |work=New Scientist |archive-date=26 August 2023 |archive-url=https://web.archive.org/web/20230826150724/https://www.newscientist.com/article/2304997-phage-therapies-for-superbug-infections-are-being-tested-in-belgium/ |url-status=live }}{{cite journal | vauthors = Eskenazi A, Lood C, Wubbolts J, Hites M, Balarjishvili N, Leshkasheli L, Askilashvili L, Kvachadze L, van Noort V, Wagemans J, Jayankura M, Chanishvili N, de Boer M, Nibbering P, Kutateladze M, Lavigne R, Merabishvili M, Pirnay JP | display-authors = 6 | title = Combination of pre-adapted bacteriophage therapy and antibiotics for treatment of fracture-related infection due to pandrug-resistant Klebsiella pneumoniae | journal = Nature Communications | volume = 13 | issue = 1 | pages = 302 | date = January 2022 | pmid = 35042848 | doi = 10.1038/s41467-021-27656-z | pmc = 8766457 | bibcode = 2022NatCo..13..302E }} The scientists called for scaling up the research{{cite news | vauthors = Hoferichter A | date = 19 January 2022 | title = Mit Viren gegen Bakterien – Bakteriophagen-Therapie als Hoffnung gegen multiresistente Keime | trans-title = With viruses against bacteria – bacteriophage therapy as a hope against multi-resistant germs | url = https://www.deutschlandfunk.de/bakteriophagen-killen-viren-100.html | access-date = 14 February 2022 | work = Deutschlandfunk | language = de | archive-date = 14 February 2022 | archive-url = https://web.archive.org/web/20220214182214/https://www.deutschlandfunk.de/bakteriophagen-killen-viren-100.html | url-status = live }} and for further development of this approach.{{cite news |vauthors=Yirka B |title=Using a bacteriophage to successfully treat a patient infected with a drug-resistant bacteria |url=https://medicalxpress.com/news/2022-01-bacteriophage-successfully-patient-infected-drug-resistant.html |access-date=14 February 2022 |work=medicalxpress.com |quote=The researchers suggest that bacteriophage therapy is a viable treatment for bacterial infections, though they note that before it can be considered as an alternative therapy for infected patients, a better means of finding bacteriophages must be found. |archive-date=14 February 2022 |archive-url=https://web.archive.org/web/20220214182216/https://medicalxpress.com/news/2022-01-bacteriophage-successfully-patient-infected-drug-resistant.html |url-status=live }}

File:Phage Therapy biofilm.webp

Phage therapy is being used to great effect in the treatment of biofilm infections, especially Pseudomonas aeruginosa and Staphylococcus aureus.{{cite journal | vauthors = Pires DP, Meneses L, Brandão AC, Azeredo J | title = An overview of the current state of phage therapy for the treatment of biofilm-related infections | journal = Current Opinion in Virology | volume = 53 | pages = 101209 | date = April 2022 | pmid = 35240424 | doi = 10.1016/j.coviro.2022.101209 | s2cid = 247180890 | doi-access = free | url = https://biblio.ugent.be/publication/01HW0T4TH8NGYS2ZJF2ABDCDQ0/file/01HW0T96E8KANW6Q33K2VPJ3N4.pdf }}{{cite journal | vauthors = Uyttebroek S, Chen B, Onsea J, Ruythooren F, Debaveye Y, Devolder D, Spriet I, Depypere M, Wagemans J, Lavigne R, Pirnay JP, Merabishvili M, De Munter P, Peetermans WE, Dupont L, Van Gerven L, Metsemakers WJ | display-authors = 6 | title = Safety and efficacy of phage therapy in difficult-to-treat infections: a systematic review | journal = The Lancet. Infectious Diseases | volume = 22 | issue = 8 | pages = e208–e220 | date = August 2022 | pmid = 35248167 | doi = 10.1016/S1473-3099(21)00612-5 | s2cid = 247251901 }} From 78 recent cases of treatment of biofilm infections, 96% of patients saw clinical improvement using phage therapy, and 52% of patients saw complete symptom relief or a full expungement of the affecting bacteria. Biofilm infections are very challenging to treat with antibiotics. The biofilm matrix and surrounding bacterial membranes can bind to the antibiotics, preventing them from penetrating the biofilm. The matrix may contain enzymes that deactivate antibiotics. Biofilms also have low metabolic activity, which means antibiotics that target growing processes have much lower efficacy. These factors make phage therapy an enticing option for the treatment of such infections, and there are currently two ways to go about such treatment. The first is to isolate the initial bacteria and make a specific treatment phage to target it, while the second way is to use a combination of more general phages. The advantage of the second method is that it can easily be made commercially available for treatment, although there are some concerns that it may be substantially less effective.File:Phage therapy 2.jpg

{{original research|section|date=February 2023}}

The high bacterial strain specificity of phage therapy may make it necessary for clinics to make different cocktails for treatment of the same infection or disease, because the bacterial components of such diseases may differ from region to region or even person to person. In addition, this means that "banks" containing many different phages must be kept and regularly updated with new phages.

Further, bacteria can evolve different receptors either before or during treatment. This can prevent phages from completely eradicating them.

The need for banks of phages makes regulatory testing for safety harder and more expensive under current rules in most countries. Such a process would make the large-scale use of phage therapy difficult. Additionally, patent issues (specifically on living organisms) may complicate distribution for pharmaceutical companies wishing to have exclusive rights over their "invention", which would discourage a commercial corporation from investing capital in this.{{medical citation needed|date=November 2024}}

As has been known for at least thirty years, mycobacteria such as Mycobacterium tuberculosis have specific bacteriophages. No lytic phage has yet been discovered for Clostridioides difficile, which is responsible for many nosocomial diseases, but some temperate phages (integrated in the genome, also called lysogenic) are known for this species; this opens encouraging avenues but with additional risks, as discussed below.

The negative public perception of viruses may contribute to the reluctance to embrace phage therapy.

One of the major concerns usually associated with phage therapy is the emergence of bacteriophage-insensitive mutants (BIMs) that could hinder the success of this therapy. Several in vitro studies have reported a fast emergence of BIMs within a short time after phage treatment.{{cite journal | vauthors = Fu W, Forster T, Mayer O, Curtin JJ, Lehman SM, Donlan RM | title = Bacteriophage cocktail for the prevention of biofilm formation by Pseudomonas aeruginosa on catheters in an in vitro model system | journal = Antimicrobial Agents and Chemotherapy | volume = 54 | issue = 1 | pages = 397–404 | date = January 2010 | pmid = 19822702 | pmc = 2798481 | doi = 10.1128/AAC.00669-09 }}{{cite journal | vauthors = Pires DP, Dötsch A, Anderson EM, Hao Y, Khursigara CM, Lam JS, Sillankorva S, Azeredo J | display-authors = 6 | title = A Genotypic Analysis of Five P. aeruginosa Strains after Biofilm Infection by Phages Targeting Different Cell Surface Receptors | journal = Frontiers in Microbiology | volume = 8 | pages = 1229 | date = 2017 | pmid = 28713356 | pmc = 5492357 | doi = 10.3389/fmicb.2017.01229 | doi-access = free }}{{cite journal | vauthors = Le S, Yao X, Lu S, Tan Y, Rao X, Li M, Jin X, Wang J, Zhao Y, Wu NC, Lux R, He X, Shi W, Hu F | display-authors = 6 | title = Chromosomal DNA deletion confers phage resistance to Pseudomonas aeruginosa | journal = Scientific Reports | volume = 4 | pages = 4738 | date = April 2014 | pmid = 24770387 | pmc = 4001099 | doi = 10.1038/srep04738 | bibcode = 2014NatSR...4.4738L }} The emergence of BIMs has also been observed in vivo using different animal models, although this usually occurs later than in vitro (reviewed in {{cite journal | vauthors = Oechslin F | title = Resistance Development to Bacteriophages Occurring during Bacteriophage Therapy | journal = Viruses | volume = 10 | issue = 7 | date = June 2018 | page = 351 | pmid = 29966329 | pmc = 6070868 | doi = 10.3390/v10070351 | doi-access = free }}). This fast adaptation of bacteria to phage attack is usually caused by mutations on genes encoding phage receptors,{{cite journal | vauthors = Oechslin F, Piccardi P, Mancini S, Gabard J, Moreillon P, Entenza JM, Resch G, Que YA | display-authors = 6 | title = Synergistic Interaction Between Phage Therapy and Antibiotics Clears Pseudomonas Aeruginosa Infection in Endocarditis and Reduces Virulence | journal = The Journal of Infectious Diseases | volume = 215 | issue = 5 | pages = 703–712 | date = March 2017 | pmid = 28007922 | pmc = 5388299 | doi = 10.1093/infdis/jiw632 }} which include lipopolysaccharides (LPS), outer membrane proteins, capsules, flagella, and pili, among others.{{cite journal | vauthors = Bertozzi Silva J, Storms Z, Sauvageau D | title = Host receptors for bacteriophage adsorption | journal = FEMS Microbiology Letters | volume = 363 | issue = 4 | date = February 2016 | pages = fnw002 | pmid = 26755501 | doi = 10.1093/femsle/fnw002 | doi-access = free }} However, some studies suggest that when phage resistance is caused by mutations in phage receptors, this might result in fitness costs to the resistance bacterium, which will ultimately become less virulent.{{cite journal | vauthors = León M, Bastías R | title = Virulence reduction in bacteriophage resistant bacteria | language = English | journal = Frontiers in Microbiology | volume = 6 | pages = 343 | date = 2015 | pmid = 25954266 | doi = 10.3389/fmicb.2015.00343 | pmc = 4407575 | doi-access = free }} Moreover, it has been shown that the evolution of bacterial resistance to phage attack changes the efflux pump mechanism, causing increased sensitivity to drugs from several antibiotic classes.{{cite journal | vauthors = Chan BK, Sistrom M, Wertz JE, Kortright KE, Narayan D, Turner PE | title = Phage selection restores antibiotic sensitivity in MDR Pseudomonas aeruginosa | journal = Scientific Reports | volume = 6 | issue = 1 | pages = 26717 | date = May 2016 | pmid = 27225966 | pmc = 4880932 | doi = 10.1038/srep26717 | bibcode = 2016NatSR...626717C }} Therefore, it is conceivable to think that phage therapy that uses phages that exert selection for multidrug-resistant bacteria to become antibiotic-sensitive could potentially reduce the incidence of antibiotic-resistant infections.{{medical citation needed|date=November 2024}}

Besides the prevention of phage adsorption by loss or modification of bacterial receptors, phage insensitivity can be caused by: prevention of phage DNA entry by superinfection exclusion systems; or degradation of phage DNA by restriction-modification systems or by CRISPR-Cas systems; and use of abortive infection systems that block phage replication, transcription, or translation, usually in conjunction with suicide of the host cell.{{cite journal | vauthors = Labrie SJ, Samson JE, Moineau S | title = Bacteriophage resistance mechanisms | journal = Nature Reviews. Microbiology | volume = 8 | issue = 5 | pages = 317–327 | date = May 2010 | pmid = 20348932 | doi = 10.1038/nrmicro2315 | s2cid = 205497795 }} Altogether, these mechanisms promote a quick adaptation of bacteria to phage attack and therefore, the emergence of phage-resistant mutants is frequent and unavoidable.{{medical citation needed|date=November 2024}}

It is still unclear whether the wide use of phages would cause resistance similar to what has been observed for antibiotics. In theory, this is not very likely to occur, since phages are very specific, and therefore, their selective pressure would affect a very narrow group of bacteria. However, we should also consider the fact that many phage resistance systems are mounted on mobile genetic elements, including prophages and plasmids, and thus may spread quite rapidly even without direct selection. Nevertheless, in contrast to antibiotics, phage preparations for therapeutic applications are expected to be developed in a personalized way because of the high specificity of phages. In addition, strategies have been proposed to counter the problem of phage resistance. One of the strategies is the use of phage cocktails with complementary host ranges (different host ranges, which, when combined, result in an overall broader host range) and targeting different bacterial receptors. Another strategy is the combination of phages with other antimicrobials such as antibiotics, disinfectants, or enzymes that could enhance their antibacterial activity. The genetic manipulation of phage genomes can also be a strategy to circumvent phage resistance.{{medical citation needed|date=November 2024}}

Bacteriophages are bacterial viruses, evolved to infect bacterial cells. To do that, phages must use characteristic structures at cell surfaces (receptors), and to propagate they need appropriate molecular tools inside the cells. Bacteria are prokaryotes, and their cells differ substantially from eukaryotes, including humans or animals.{{Cite news |vauthors=Pedersen T, Dutfield S |date=18 January 2022 |title=Prokaryotic vs. Eukaryotic Cells: What's the Difference? |url=https://www.livescience.com/65922-prokaryotic-vs-eukaryotic-cells.html |access-date=15 March 2022 |website=livescience.com |archive-date=26 August 2023 |archive-url=https://web.archive.org/web/20230826150751/https://www.livescience.com/65922-prokaryotic-vs-eukaryotic-cells.html |url-status=live }} For this reason, phages meet the major safety requirement: they do not infect treated individuals. Even engineered phages and induced artificial internalization of phages into mammalian cells do not result in phage propagation.{{cite journal | vauthors = Di Giovine M, Salone B, Martina Y, Amati V, Zambruno G, Cundari E, Failla CM, Saggio I | display-authors = 6 | title = Binding properties, cell delivery, and gene transfer of adenoviral penton base displaying bacteriophage | journal = Virology | volume = 282 | issue = 1 | pages = 102–112 | date = March 2001 | pmid = 11259194 | doi = 10.1006/viro.2000.0809 | doi-access = free }} Natural transcytosis of unmodified phages, that is, uptake and internal transport to the other side of a cell, which was observed in human epithelial cells, did not result in phage propagation or cell damage.{{cite journal | vauthors = Nguyen S, Baker K, Padman BS, Patwa R, Dunstan RA, Weston TA, Schlosser K, Bailey B, Lithgow T, Lazarou M, Luque A, Rohwer F, Blumberg RS, Barr JJ | display-authors = 6 | title = Bacteriophage Transcytosis Provides a Mechanism to Cross Epithelial Cell Layers | journal = mBio | volume = 8 | issue = 6 | date = November 2017 | pmid = 29162715 | pmc = 5698557 | doi = 10.1128/mBio.01874-17 }} Recently, however, it was reported that filamentous temperate phages of P. aeruginosa can be endocytosed into human and murine leukocytes, resulting in transcription of the phage DNA. In turn, the product RNA triggers maladaptive innate viral pattern-recognition responses and thus inhibits the immune clearance of the bacteria.{{cite journal | vauthors = Sweere JM, Van Belleghem JD, Ishak H, Bach MS, Popescu M, Sunkari V, Kaber G, Manasherob R, Suh GA, Cao X, de Vries CR, Lam DN, Marshall PL, Birukova M, Katznelson E, Lazzareschi DV, Balaji S, Keswani SG, Hawn TR, Secor PR, Bollyky PL | display-authors = 6 | title = Bacteriophage trigger antiviral immunity and prevent clearance of bacterial infection | journal = Science | volume = 363 | issue = 6434 | pages = eaat9691 | date = March 2019 | pmid = 30923196 | pmc = 6656896 | doi = 10.1126/science.aat9691 }} Whether this also applies to dsDNA phages like Caudovirales has not yet been established; this is an important question to be addressed as it may affect the overall safety of phage therapy.{{medical citation needed|date=November 2024}}

Due to many experimental treatments in human patients conducted in past decades, and to already existing RCTs (see section: Clinical experience and randomized controlled trials), phage safety can be assessed directly. The first safety trial in healthy human volunteers for a phage was conducted by Bruttin and Brüssow in 2005.{{cite journal | vauthors = Bruttin A, Brüssow H | title = Human volunteers receiving Escherichia coli phage T4 orally: a safety test of phage therapy | journal = Antimicrobial Agents and Chemotherapy | volume = 49 | issue = 7 | pages = 2874–2878 | date = July 2005 | pmid = 15980363 | pmc = 1168693 | doi = 10.1128/AAC.49.7.2874-2878.2005 }} They investigated the oral administration of Escherichia coli phage T4 and found no adverse effects of the treatment.{{medical citation needed|date=November 2024}}

Historical record shows that phages are safe, with mild side effects, if any. Still, administering bacteriophages can induce an immune response.{{cite journal |last=Dąbrowska |first=Katarzyna |title=Phage therapy: what factors shape phage pharmacokinetics and bioavailability? |journal=Systematic and Applied Microbiology |volume=42 |issue=3 |pages=158–164 |year=2019 |doi=10.1016/j.syapm.2018.08.013 |pmid=30238806}} Macrophages, key cells of the innate immune system, play a central role in mediating this response.{{cite journal |last1=Richards |first1=Paul |last2=Mrsny |first2=Randall J. |last3=Cuella-Kennedy |first3=Roland |title=Innovations in Therapeutic Bacteriophage Development: From Bench to Bedside |journal=Frontiers in Pharmacology |volume=12 |year=2021 |doi=10.3389/fimmu.2021.615539 |doi-access=free |pmid=33767696|pmc=7985326 }} The most frequent (though still rare) adverse reactions to phage preparations found in patients were symptoms from the digestive tract, local reactions at the site of administration of a phage preparation, superinfections, and a rise in body temperature.{{cite book | vauthors = Międzybrodzki R, Borysowski J, Weber-Dąbrowska B, Fortuna W, Letkiewicz S, Szufnarowski K, Pawełczyk Z, Rogóż P, Kłak M, Wojtasik E, Górski A | title = Bacteriophages, Part B | chapter = Clinical Aspects of Phage Therapy | series = Advances in Virus Research | display-authors = 6 | volume = 83 | pages = 73–121 | date = 2012 | pmid = 22748809 | doi = 10.1016/B978-0-12-394438-2.00003-7 | isbn = 978-0-12-394438-2 }}{{cite journal | vauthors = Speck P, Smithyman A | title = Safety and efficacy of phage therapy via the intravenous route | journal = FEMS Microbiology Letters | volume = 363 | issue = 3 | date = February 2016 | pages = fnv242 | pmid = 26691737 | doi = 10.1093/femsle/fnv242 | doi-access = free }} These reactions might have occurred because either toxins were released from bacteria destroyed by the phages{{cite journal |last1=Dąbrowska |first1=Katarzyna |title=Phage Therapy: What Factors Shape Phage Pharmacokinetics and Bioavailability? |journal=Systematic and Applied Microbiology |volume=42 |issue=5 |year=2019 |pages=158–164 |doi=10.1016/j.syapm.2018.08.011 |pmid=30238806}}{{cite journal |last1=Uchiyama |first1=Jiro |last2=Maeda |first2=Yoshihito |last3=Takemura-Uchiyama |first3=Ikoma |last4=Satoh |first4=Masaru |last5=Kato |first5=Satoshi |last6=Wakiguchi |first6=Hiroyuki |last7=Matsuzaki |first7=Shigenori |title=Purification of Bacteriophages by Fractionated Precipitation with Polyethylene Glycol 6000 |journal=Frontiers in Microbiology |volume=9 |year=2018 |pages=275–282 |doi=10.3389/fmicb.2018.00325 |doi-access=free |pmid=29535543|pmc=5836672 }}—such toxin release from bacteria can also happen with antibiotic use{{cite journal | vauthors = Prins JM, van Deventer SJ, Kuijper EJ, Speelman P | title = Clinical relevance of antibiotic-induced endotoxin release | journal = Antimicrobial Agents and Chemotherapy | volume = 38 | issue = 6 | pages = 1211–1218 | date = June 1994 | pmid = 8092816 | doi = 10.1128/aac.38.6.1211 | pmc = 188188 }}—or due to leftover bacterial fragments or residual components from the bacterial growth medium ("food for bacteria") present in the phage treatment when unpurified preparations were used.{{cite journal |last1=Vitiello |first1=Claudia L. |last2=Evans |first2=Brooke A. |last3=Kutter |first3=Elizabeth |last4=Salas |first4=Melinda L. |last5=D'Amico |first5=Francesco |title=Phage Therapy: Compassionate Use of Bacteriophages against Antimicrobial-Resistant Pseudomonas aeruginosa Infections in 30 Patients |journal=American Journal of Infection Control |volume=50 |issue=7 |year=2022 |pages=798–806 |doi=10.1016/j.ajic.2021.03.004 |pmid=33831984|doi-access=free }}{{cite journal |last1=Jun |first1=Soo-Kyoung |last2=Yoon |first2=Young |last3=Jang |first3=Ilsu |last4=Chae |first4=Youhei |last5=Kim |first5=Won Seok |title=Purification of Bacteriophages for Phage Therapy and Characterization of Staphylococcus aureus Phage SA97 |journal=Viruses |volume=13 |issue=6 |year=2021 |doi=10.3390/v13061161 |doi-access=free |pmid=34201035|pmc=8228364 }}

When bacteriophages are introduced into the body, they may be recognized as foreign entities by macrophages through pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs).{{cite journal |last1=Borysowski |first1=Jacek |last2=Górski |first2=Andrzej |title=Phage therapy in the era of antimicrobial resistance: correlations between pharmacodynamic parameters and phage therapy effectiveness |journal=Current Pharmaceutical Biotechnology |volume=11 |issue=1 |pages=150–157 |year=2010 |doi=10.2174/138920110790725302 |pmid=20214609}} The binding of bacteriophages to these receptors triggers macrophage activation, leading to phagocytosis (macrophages engulf and digest the bacteriophages){{cite journal |last1=Sweere |first1=Jaimie M. |last2=Van Belleghem |first2=Jonah D. |last3=Iglesias |first3=Devin |title=Bacteriophage trigger antiviral immunity and prevent clearance of bacterial infection |journal=Science |volume=363 |issue=6434 |pages=1085–1102 |year=2019 |doi=10.1126/science.aat9691 |pmid=30733383|pmc=6469404 }} and cytokine production: activated macrophages produce pro-inflammatory cytokines.{{cite journal |last1=Leung |first1=Samuel S. Y. |last2=Parumasivam |first2=T. |last3=Kibiloski |first3=Scott |title=Bacteriophages in the control of multidrug-resistant Pseudomonas aeruginosa infections |journal=Journal of Applied Microbiology |volume=128 |issue=1 |pages=16–24 |year=2020 |doi=10.1111/jam.14427 |pmid=31300853}} These cytokines can modulate the immune response but generally do not result in significant fever when phages are used appropriately.

The route by which bacteriophages enter the body can affect the degree of immune activation.{{cite journal |last1=Górski |first1=Andrzej |last2=Borysowski |first2=Jacek |last3=Miecielica-Pawłowska |first3=Aneta |title=Potential of phage therapy in autoimmune diseases |journal=Frontiers in Immunology |volume=3 |year=2012 |issue=4 |pages=253–260 |doi=10.3389/fimmu.2012.00368 |doi-access=free |pmid=23133459|pmc=3490526 }} Applying bacteriophages directly to the mucosa targets the site of infection with minimal systemic exposure, leading to a localized immune response.{{cite journal |last1=Miettinen |first1=Satu M. |last2=Kalliomäki |first2=Marjut |last3=Korpela |first3=Katri |title=Temporal changes in nasal microbiota and their association with asthma in early childhood |journal=European Respiratory Journal |volume=54 |issue=3 |pages=1003–1005 |year=2019 |doi=10.1183/13993003.01320-2019 |pmid=31371324|pmc=6949509 }} Injecting bacteriophages into muscle tissue introduces them to a larger number of macrophages in the muscle and regional lymph nodes.{{cite journal |last1=Hawkins |first1=Christina |last2=Harvey |first2=Edward |last3=Kaatz |first3=Glenn W. |title=Bacteriophage therapy for refractory Pseudomonas aeruginosa urinary tract infection |journal=Journal of Medical Microbiology |volume=59 |issue=Pt 9 |pages=1137–1140 |year=2010 |doi=10.1099/jmm.0.022939-0 |pmid=20576768}} In intravenous injection, direct introduction into the bloodstream exposes bacteriophages to macrophages throughout the body, including those in the spleen and liver.{{cite journal |last1=Petrovic Fabijan |first1=Nina |last2=Barrera |first2=Kara |last3=Kirkpatrick |first3=Peter |title=Safety of bacteriophage therapy in severe Staphylococcus aureus infection |journal=Nature Microbiology |volume=5 |issue=3 |pages=465–472 |year=2020 |doi=10.1038/s41564-019-0634-z |pmid=32066944}} However, significant elevations in body temperature are uncommon and typically only observed in cases of rapid phage administration or high doses. Anticipating immune responses allows healthcare professionals to monitor patients appropriately and make treatment adjustments if necessary.{{cite book|language = ru|trans-title=Bacteriophage Treatment of Wounds|title=Лечение ран бактериофагом|author1=Покровская М. П. |author2=Каганова Л. С.|author3=Морозенко М. А.|publisher=Медгиз|year=1941}}{{cite journal |last1=Ujjain |first1=Swami M. |last2=Singh |first2=Vinod Kumar |last3=Dhawan |first3=Bijoy Chand |title=Bacteriophage therapy: A potential solution for the antibiotic resistance crisis |journal=Medical Journal Armed Forces India |volume=75 |issue=1 |pages=2–4 |year=2019 |doi=10.1016/j.mjafi.2018.12.010 |pmid=30815173 |pmc=6376917}} Macrophages are integral to the body's immune response to bacteriophage therapy, mediating any potential immune reactions.{{cite journal |last=Abedon |first=Stephen T. |title=Information phage therapy research should report |journal=Phage |volume=2 |issue=1 |pages=e1252593 |year=2021 |doi=10.1080/21597081.2021.1252593 |doi-broken-date=2024-11-23 |pmid=33816791|pmc=8015635 }} Intravenous administration of bacteriophages is conducted under strict medical supervision, by specialists in infectious diseases within a hospital setting, due to potential adverse reactions.{{cite journal |last1=Abedon |first1=Stephen T. |title=Information Phage Therapy Research Should Report |journal=Phage |volume=1 |issue=3 |year=2020 |pages=1–4 |doi=10.1016/j.jhsg.2020.09.002 |pmid=32954231 |pmc=7486043 }} Adverse reactions to intravenous bacteriophage therapy may include hypotension, i.e., a drop in blood pressure, leading to loss of consciousness.{{cite journal |last1=Rhoads |first1=Daniel D. |last2=Wolcott |first2=Robert D. |last3=Khoruts |first3=Alexander |title=Bacteriophage Therapy of Venous Leg Ulcers in Humans: Results of a Phase I Safety Trial |journal=Journal of Wound Care |volume=18 |issue=6 |year=2009 |pages=237–243 |doi=10.12968/jowc.2009.18.6.42801 |pmid=19543108}} A sudden drop (chills) and rise (fever) in body temperature, known as the Jarisch–Herxheimer reaction, can occur due to the rapid lysis of bacteria and release of endotoxins.{{cite journal |last1=Kutateladze |first1=Marianna |last2=Adamia |first2=Revaz |title=Phage Therapy Experience at the Eliava Institute |journal=Médecine et Maladies Infectieuses |volume=38 |issue=8 |year=2008 |pages=426–430 |doi=10.1016/j.medmal.2008.06.023 |pmid=18674822}} Rapid bacterial lysis releases endotoxins (e.g., lipopolysaccharides from gram-negative bacteria) that trigger systemic inflammatory responses,{{cite journal |last1=Sybesma |first1=Wieke |last2=Zbinden |first2=Raffael |last3=Chanishvili |first3=Nino |title=Draft Guidance on Personalized Phage Therapy |journal=Nature Biotechnology |volume=36 |issue=7 |year=2018 |pages=666–668 |doi=10.1038/nbt.4226 |pmid=29967538|pmc=6045459 }} including "cytokine storms".{{cite journal |last1=McCallin |first1=Stephan |last2=Sauvageau |first2=Dominique |last3=Sprung |first3=Christoph |last4=Burrowes |first4=Ben |title=Phage Therapy Needs a Clinical Boost |journal=Viruses |volume=11 |issue=9 |year=2019 |page=815 |doi=10.3390/v11090815 |doi-access=free |pmid=31466318|pmc=6749586 }} Continuous monitoring of heart rate, blood pressure, and temperature to detect early signs of adverse reactions is done after the intravenous phage administration.{{cite book |last1=Harbarth |first1=Stephan |last2=Ebbing Lautenbach |title=Antibiotic Policies: Fighting Resistance |publisher=Springer |date=19 August 2007 |pages=567–584 |isbn=978-0-387-70841-6}}{{cite journal |last1=Petrovic Fabijan |first1=Nina |last2=Khalid |first2=Ali |last3=Roux |first3=David |title=Adjunctive Bacteriophage Therapy for Treatment of Staphylococcus aureus Bacteremia |journal=Clinical Infectious Diseases |volume=70 |issue=12 |year=2020 |pages=2528–2535 |doi=10.1093/cid/ciz892 |pmid=31556465|pmc=7309189 }} Successful treatment of life-threatening infections with intravenous phage therapy has been documented.{{cite journal |last1=Dedrick |first1=Rachel M. |last2=Gupta |first2=Khushbu |last3=Saima |first3=Septien |title=Engineered Bacteriophages for Treatment of a Patient with a Disseminated Drug-Resistant Mycobacterium abscessus |journal=Nature Medicine |volume=25 |issue=5 |year=2019 |pages=730–733 |doi=10.1038/s41591-019-0437-z |pmid=31068720|pmc=6557439 }} Patients have responded to therapy after one or several intravenous administrations, clearing infections that were unresponsive to conventional treatments:{{cite journal |last1=Chan |first1=Benjamin K. |last2=Abedon |first2=Stephen T. |last3=Loc-Carrillo |first3=Catherine |title=Phage Cocktails and the Future of Phage Therapy |journal=Future Microbiology |volume=8 |issue=6 |year=2013 |pages=769–783 |doi=10.2217/fmb.13.47 |pmid=23701332|doi-access=free }} phages can disrupt biofilms, which are often resistant to antibiotics, enhancing infection clearance.{{cite journal |last1=Fish |first1=Rachel |last2=Kutter |first2=Elizabeth |last3=Wright |first3=Aveline |last4=Slopek |first4=Sylwia |title=Bacteriophage Treatment of Intransigent Diabetic Toe Ulcers: A Case Series |journal=Journal of Wound Care |volume=25 |issue=S7 |year=2016 |pages=S27–S33 |doi=10.12968/jowc.2016.25.Sup7.S27 |pmid=27633613|pmc=5558513 }}

Bacteriophages must be produced in bacteria that are lysed (i.e., fragmented) during phage propagation. As such, phage lysates contain bacterial debris that may affect the human organism even when the phage itself is harmless. For these and other reasons, purification of bacteriophages is considered important, and phage preparations need to be assessed for their safety as a whole, particularly when phages are to be administered intravenously. This is consistent with general procedures for other drug candidates. In 2015, a group of phage therapy experts summarized the quality and safety requirements for sustainable phage therapy.{{cite journal | vauthors = Pirnay JP, Blasdel BG, Bretaudeau L, Buckling A, Chanishvili N, Clark JR, Corte-Real S, Debarbieux L, Dublanchet A, De Vos D, Gabard J, Garcia M, Goderdzishvili M, Górski A, Hardcastle J, Huys I, Kutter E, Lavigne R, Merabishvili M, Olchawa E, Parikka KJ, Patey O, Pouilot F, Resch G, Rohde C, Scheres J, Skurnik M, Vaneechoutte M, Van Parys L, Verbeken G, Zizi M, Van den Eede G | display-authors = 6 | title = Quality and safety requirements for sustainable phage therapy products | journal = Pharmaceutical Research | volume = 32 | issue = 7 | pages = 2173–2179 | date = July 2015 | pmid = 25585954 | pmc = 4452253 | doi = 10.1007/s11095-014-1617-7 }}

Phage effects on the human microbiome also contribute to safety issues in phage therapy. Many phages, especially temperate ones, carry genes that can affect the pathogenicity of the host. Even lambda, a temperate phage of the E. coli K-12 laboratory strain, carries two genes that provide potential virulence benefits to the lysogenic host, one that increases intestinal adherence and the other that confers resistance to complement killing in the blood. For this reason, temperate phages are generally to be avoided as candidates for phage therapy, although in some cases, the lack of lytic phage candidates and emergency conditions may make such considerations moot.{{cite journal | vauthors = Dedrick RM, Guerrero-Bustamante CA, Garlena RA, Russell DA, Ford K, Harris K, Gilmour KC, Soothill J, Jacobs-Sera D, Schooley RT, Hatfull GF, Spencer H | display-authors = 6 | title = Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus | journal = Nature Medicine | volume = 25 | issue = 5 | pages = 730–733 | date = May 2019 | pmid = 31068712 | pmc = 6557439 | doi = 10.1038/s41591-019-0437-z }} Another potential problem is generalized transduction, a term for the ability of some phages to transfer bacterial DNA from one host to another. This occurs because the systems for packaging of the phage DNA into capsids can mistakenly package host DNA instead. Indeed, with some well-characterized phages, up to 5% of the virus particles contain only bacterial DNA. Thus in a typical lysate, the entire genome of the propagating host is present in more than a million copies in every milliliter. For these reasons, it is imperative that any phage to be considered for therapeutic usage should be subjected to thorough genomic analysis and tested for the capacity for generalized transduction.{{citation needed|date=February 2023}}

As antibacterials, phages may also affect the composition of microbiomes, by infecting and killing phage-sensitive strains of bacteria. However, a major advantage of bacteriophages over antibiotics is the high specificity of bacteriophages. This specificity limits antibacterial activity to a sub-species level; typically, a phage kills only selected bacterial strains. For this reason, phages are much less likely (than antibiotics) to disturb the composition of a natural microbiome or to induce dysbiosis. This was demonstrated in experimental studies where microbiome composition was assessed by next-generation sequencing that revealed no important changes correlated with phage treatment in human treatments.{{cite journal | vauthors = Sarker SA, Berger B, Deng Y, Kieser S, Foata F, Moine D, Descombes P, Sultana S, Huq S, Bardhan PK, Vuillet V, Praplan F, Brüssow H | display-authors = 6 | title = Oral application of Escherichia coli bacteriophage: safety tests in healthy and diarrheal children from Bangladesh | journal = Environmental Microbiology | volume = 19 | issue = 1 | pages = 237–250 | date = January 2017 | pmid = 27750388 | doi = 10.1111/1462-2920.13574 | bibcode = 2017EnvMi..19..237S | s2cid = 30583654 }}{{cite journal | vauthors = McCallin S, Sarker SA, Sultana S, Oechslin F, Brüssow H | title = Metagenome analysis of Russian and Georgian Pyophage cocktails and a placebo-controlled safety trial of single phage versus phage cocktail in healthy Staphylococcus aureus carriers | journal = Environmental Microbiology | volume = 20 | issue = 9 | pages = 3278–3293 | date = September 2018 | pmid = 30051571 | doi = 10.1111/1462-2920.14310 | bibcode = 2018EnvMi..20.3278M | s2cid = 51725081 }}{{cite journal | vauthors = Sarker SA, McCallin S, Barretto C, Berger B, Pittet AC, Sultana S, Krause L, Huq S, Bibiloni R, Bruttin A, Reuteler G, Brüssow H | display-authors = 6 | title = Oral T4-like phage cocktail application to healthy adult volunteers from Bangladesh | journal = Virology | volume = 434 | issue = 2 | pages = 222–232 | date = December 2012 | pmid = 23102968 | doi = 10.1016/j.virol.2012.09.002 | doi-access = free }}{{cite journal | vauthors = Sarker SA, Sultana S, Reuteler G, Moine D, Descombes P, Charton F, Bourdin G, McCallin S, Ngom-Bru C, Neville T, Akter M, Huq S, Qadri F, Talukdar K, Kassam M, Delley M, Loiseau C, Deng Y, El Aidy S, Berger B, Brüssow H | display-authors = 6 | title = Oral Phage Therapy of Acute Bacterial Diarrhea with Two Coliphage Preparations: A Randomized Trial in Children from Bangladesh | journal = eBioMedicine | volume = 4 | pages = 124–137 | date = February 2016 | pmid = 26981577 | pmc = 4776075 | doi = 10.1016/j.ebiom.2015.12.023 }}{{cite journal | vauthors = Galtier M, De Sordi L, Maura D, Arachchi H, Volant S, Dillies MA, Debarbieux L | title = Bacteriophages to reduce gut carriage of antibiotic resistant uropathogens with low impact on microbiota composition | journal = Environmental Microbiology | volume = 18 | issue = 7 | pages = 2237–2245 | date = July 2016 | pmid = 26971586 | doi = 10.1111/1462-2920.13284 | bibcode = 2016EnvMi..18.2237G | s2cid = 22746141 | doi-access = free | url = https://hal-pasteur.archives-ouvertes.fr/pasteur-01538960/file/Galtier_et_al-2016-Environmental_Microbiology.pdf }}{{cite journal | vauthors = Majewska J, Kaźmierczak Z, Lahutta K, Lecion D, Szymczak A, Miernikiewicz P, Drapała J, Harhala M, Marek-Bukowiec K, Jędruchniewicz N, Owczarek B, Górski A, Dąbrowska K | display-authors = 6 | title = Induction of Phage-Specific Antibodies by Two Therapeutic Staphylococcal Bacteriophages Administered per os | journal = Frontiers in Immunology | volume = 10 | pages = 2607 | date = 2019 | pmid = 31803179 | pmc = 6871536 | doi = 10.3389/fimmu.2019.02607 | doi-access = free }}

Much of the difficulty in obtaining regulatory approval is proving to be the risks of using a self-replicating entity that has the capability to evolve.

As with antibiotic therapy and other methods of countering bacterial infections, endotoxins are released by the bacteria as they are destroyed within the patient (Jarisch–Herxheimer reaction). This can cause symptoms of fever; in extreme cases, toxic shock (a problem also seen with antibiotics) is possible. Janakiraman Ramachandran argues that this complication can be avoided in those types of infection where this reaction is likely to occur by using genetically engineered bacteriophages that have had their gene responsible for producing endolysin removed. Without this gene, the host bacterium still dies but remains intact, because the lysis is disabled. On the other hand, this modification stops the exponential growth of phages, so one administered phage means at most one dead bacterial cell. Eventually, these dead cells are consumed by the normal house-cleaning duties of the phagocytes, which utilize enzymes to break down the whole bacterium and its contents into harmless proteins, polysaccharides, and lipids.

Temperate (or lysogenic) bacteriophages are not generally used therapeutically, since this group can act as a way for bacteria to exchange DNA. This can help spread antibiotic resistance or even, theoretically, make the bacteria pathogenic, such as in cases of cholera. Carl Merril has claimed that harmless strains of corynebacterium may have been converted into C. diphtheriae that "probably killed a third of all Europeans who came to North America in the seventeenth century".{{rp|94}} Fortunately, many phages seem to be lytic only with negligible probability of becoming lysogenic.

Approval of phage therapy for use in humans has not been given in Western countries, with a few exceptions. In the United States, Washington and Oregon law allows naturopathic physicians to use any therapy that is legal anywhere in the world on an experimental basis, and in Texas, phages are considered natural substances and can be used in addition to (but not as a replacement for) traditional therapy (they have been used routinely in a wound care clinic in Lubbock since 2006).

In 2013, "the 20th biennial Evergreen International Phage Meeting ... conference drew 170 participants from 35 countries, including leaders of companies and institutes involved with human phage therapies from France, Australia, Georgia, Poland, and the United States."

In France, phage therapy disappeared officially with the withdrawal of the [https://www.vidal.fr/ Vidal dictionary] (France's official drug directory), in 1978. The last phage preparation, produced by l'Institut du Bactériophage, was an ointment against skin infections. Phage therapy research ceased at about the same time across the country, with the closure of the bacteriophage department at the Pasteur Institute. Some hospital physicians continued to offer phage therapy until the 1990s, when production died out.{{cite journal | vauthors = Dublanchet A, Fruciano E | title = [A short history of phage therapy] | journal = Médecine et Maladies Infectieuses | volume = 38 | issue = 8 | pages = 415–420 | date = August 2008 | pmid = 18692974 | doi = 10.1016/j.medmal.2008.06.016 }}

On their rediscovery, at the end of the 1990s, phage preparations were classified as medicines, i.e., "medicinal products" in the EU or "drugs" in the US.{{cite journal | vauthors = Verbeken G, Pirnay JP, Lavigne R, Jennes S, De Vos D, Casteels M, Huys I | title = Call for a dedicated European legal framework for bacteriophage therapy | journal = Archivum Immunologiae et Therapiae Experimentalis | volume = 62 | issue = 2 | pages = 117–129 | date = April 2014 | pmid = 24500660 | pmc = 3950567 | doi = 10.1007/s00005-014-0269-y }} However, the pharmaceutical legislation that had been implemented since their disappearance from Western medicine was mainly designed to cater for industrially-made pharmaceuticals, devoid of any customization and intended for large-scale distribution,{{cite journal | vauthors = Fauconnier A | title = Phage Therapy Regulation: From Night to Dawn | journal = Viruses | volume = 11 | issue = 4 | date = April 2019 | page = 352 | pmid = 30999559 | pmc = 6521264 | doi = 10.3390/v11040352 | doi-access = free }} and it was not deemed necessary to provide phage-specific requirements or concessions.

Today's phage therapy products need to comply with the entire battery of medicinal product licensing requirements: manufacturing according to GMP, preclinical studies, phase I, II, and III clinical trials, and marketing authorisation. Technically, industrially produced predefined phage preparations could make it through the conventional pharmaceutical processes, minding some adaptations. However, phage specificity and resistance issues are likely to cause these defined preparations to have a relatively short useful lifespan.{{cite journal | vauthors = Pirnay JP, Verbeken G, Ceyssens PJ, Huys I, De Vos D, Ameloot C, Fauconnier A | title = The Magistral Phage | journal = Viruses | volume = 10 | issue = 2 | date = February 2018 | page = 64 | pmid = 29415431 | pmc = 5850371 | doi = 10.3390/v10020064 | doi-access = free }} The pharmaceutical industry is currently not considering phage therapy products. Yet, a handful of small and medium-sized enterprises have shown interest, with the help of risk capital and/or public funding. Currently, no defined therapeutic phage product has made it to the EU or US markets.

File:ConventionalPT vs Magistral.jpg

According to Jean-Paul Pirnay, therapeutic phages should be prepared individually and kept in large phage banks, ready to be used, upon testing for effectiveness against the patient's bacterial pathogen(s). Intermediary or combined (industrially made as well as precision phage preparations) approaches could be appropriate. However, it turns out to be difficult to reconcile classical phage therapy concepts, which are based on the timely adaptation of phage preparations, with current Western pharmaceutical R&D and marketing models. Repeated calls for a specific regulatory framework have not been heeded by European policymakers. A phage therapy framework based on the Biological Master File concept has been proposed as a (European) solution to regulatory issues, but European regulations do not allow for an extension of this concept to biologically active substances such as phages.{{cite journal | vauthors = Fauconnier A | title = Regulating phage therapy: The biological master file concept could help to overcome regulatory challenge of personalized medicines | journal = EMBO Reports | volume = 18 | issue = 2 | pages = 198–200 | date = February 2017 | pmid = 28082313 | pmc = 5286392 | doi = 10.15252/embr.201643250 }}

Meanwhile, representatives from the medical, academic, and regulatory communities have established some (temporary) national solutions. For instance, phage applications have been performed in Europe under the umbrella of Article 37 (Unproven Interventions in Clinical Practice) of the Helsinki Declaration. To enable the application of phage therapy after Poland had joined the EU in 2004, the Ludwik Hirszfeld Institute of Immunology and Experimental Therapy in Wrocław opened its own Phage Therapy Unit (PTU). Phage therapy performed at the PTU is considered an "experimental treatment", covered by the adapted Act of 5 December 1996 on the Medical Profession (Polish Law Gazette, 2011, No. 277 item 1634) and Article 37 of the Helsinki Declaration.{{cite journal | vauthors = Henein A | title = What are the limitations on the wider therapeutic use of phage? | journal = Bacteriophage | volume = 3 | issue = 2 | pages = e24872 | date = April 2013 | pmid = 24228220 | pmc = 3821673 | doi = 10.4161/bact.24872 }} Similarly, in the last few years, a number of phage therapy interventions have been performed in the US under the FDA's emergency Investigational New Drug (eIND) protocol.{{cite journal | vauthors = McCallin S, Sacher JC, Zheng J, Chan BK | title = Current State of Compassionate Phage Therapy | journal = Viruses | volume = 11 | issue = 4 | pages = 343 | date = April 2019 | pmid = 31013833 | pmc = 6521059 | doi = 10.3390/v11040343 | doi-access = free }}

Some patients have been treated with phages under the umbrella of "compassionate use", which is a treatment option that allows a physician to use a not-yet-authorized medicine in desperate cases. Under strict conditions, medicines under development can be made available for use in patients for whom no satisfactory authorized therapies are available and who cannot participate in clinical trials. In principle, this approach can only be applied to products for which earlier study results have demonstrated efficacy and safety, but have not yet been approved. Much like Article 37 of the Helsinki Declaration, the compassionate use treatment option can only be applied when the phages are expected to help in life-threatening or chronic and/or seriously debilitating diseases that are not treatable with formally approved products.{{citation needed|date=February 2023}}

In France, ANSM, the French medicine agency, has organized a specific committee—Comité Scientifique Spécialisé Temporaire (CSST)—for phage therapy, which consists of experts in various fields. Their task is to evaluate and guide each phage therapy request that ends up at the ANSM. Phage therapy requests are discussed together with the treating physicians and consensus advice is sent to the ANSM], which then decides whether or not to grant permission. Between 2006 and 2018, fifteen patients were treated in France (eleven recovered) using this pathway.{{cite journal | vauthors = Patey O, McCallin S, Mazure H, Liddle M, Smithyman A, Dublanchet A | title = Clinical Indications and Compassionate Use of Phage Therapy: Personal Experience and Literature Review with a Focus on Osteoarticular Infections | journal = Viruses | volume = 11 | issue = 1 | date = December 2018 | page = 18 | pmid = 30597868 | pmc = 6356659 | doi = 10.3390/v11010018 | doi-access = free }}

In Belgium, in 2016 and in response to a number of parliamentary questions, Maggie De Block, the Minister of Social Affairs and Health, acknowledged that it is indeed not evident to treat phages as industrially made drugs, and therefore she proposed to investigate if the magistral preparation pathway could offer a solution. Magistral preparations (compounding pharmacies in the US) are not subjected to certain constraints such as GMP compliance and marketing authorization. As the "magistral preparation framework" was created to allow for adapted patient treatments and/or to use medicines for which there is no commercial interest, it seemed a suitable framework for precision phage therapy concepts. Magistral preparations are medicines prepared in a pharmacy in accordance with a medical prescription for an individual patient. They are made by a pharmacist (or under his/her supervision) from their constituent ingredients, according to the technical and scientific standards of pharmaceutical technology. Phage active pharmaceutical ingredients to be included in magistral preparations must meet the requirements of a monograph, which describes their production and quality control testing. They must be accompanied by a certificate of analysis, issued by a "Belgian Approved Laboratory", which has been granted an accreditation to perform batch-release testing of medicinal products. Since 2019, phages have been delivered in the form of magistral preparations to nominal patients in Belgium.{{cite journal | vauthors = Pirnay JP, Verbeken G, Ceyssens PJ, Huys I, De Vos D, Ameloot C, Fauconnier A | title = The Magistral Phage | journal = Viruses | volume = 10 | issue = 2 | page = 64 | date = February 2018 | pmid = 29415431 | pmc = 5850371 | doi = 10.3390/v10020064 | doi-access = free }}

The first phage therapy case in China can be traced back to 1958, at Shanghai Jiao Tong University School of Medicine.{{cite journal | vauthors = Liang S, Qi Y, Yu H, Sun W, Raza SH, Alkhorayef N, Alkhalil SS, Salama EE, Zhang L | display-authors = 6 | title = Bacteriophage Therapy as an Application for Bacterial Infection in China | journal = Antibiotics | volume = 12 | issue = 2 | pages = 417 | date = February 2023 | pmid = 36830327 | pmc = 9952293 | doi = 10.3390/antibiotics12020417 | doi-access = free }} However, many regulations were not yet established back then, and phage therapy soon lost people's interest due to the prevalence of antibiotics, which eventually led to the antimicrobial resistance crisis. This prompted researchers in China as well as the Chinese government to pay attention to phage therapy again, and following the first investigator-initiated trial (IIT) by the Shanghai Institute of Phage in 2019, phage therapy rapidly flourished.{{cite journal | vauthors = Bao J, Wu N, Zeng Y, Chen L, Li L, Yang L, Zhang Y, Guo M, Li L, Li J, Tan D, Cheng M, Gu J, Qin J, Liu J, Li S, Pan G, Jin X, Yao B, Guo X, Zhu T, Le S | display-authors = 6 | title = Non-active antibiotic and bacteriophage synergism to successfully treat recurrent urinary tract infection caused by extensively drug-resistant Klebsiella pneumoniae | journal = Emerging Microbes & Infections | volume = 9 | issue = 1 | pages = 771–774 | date = December 2020 | pmid = 32212918 | pmc = 7170350 | doi = 10.1080/22221751.2020.1747950 }} Currently, commercial phage therapy applications must go through either one of two pathways. The first is for fixed-ingredient phage products.{{cite journal | vauthors = Lu J, Xu L, Wei W, He W | title = Advanced therapy medicinal products in China: Regulation and development | journal = MedComm | volume = 4 | issue = 3 | pages = e251 | date = June 2023 | pmid = 37125239 | pmc = 10133728 | doi = 10.1002/mco2.251 }} The second pathway is for personalized phage products, which need to go through IITs. This way, the products are considered restrictive medical technologies.{{cite journal | vauthors = Yang Q, Le S, Zhu T, Wu N | title = Regulations of phage therapy across the world | journal = Frontiers in Microbiology | volume = 14 | pages = 1250848 | date = 2023 | pmid = 37869667 | pmc = 10588630 | doi = 10.3389/fmicb.2023.1250848 | doi-access = free }}

Phage therapy has been a relevant mode of treatment in animals for decades.{{cite journal | vauthors = Squires RA | title = Bacteriophage therapy for challenging bacterial infections: achievements, limitations and prospects for future clinical use by veterinary dermatologists | journal = Veterinary Dermatology | volume = 32 | issue = 6 | pages = 587–e158 | date = December 2021 | pmid = 33870572 | doi = 10.1111/vde.12958 | s2cid = 233298262 | doi-access = free }} It has been proposed as a method of treating bacterial infections in the veterinary medical field in response to the rampant use of antibiotics. Studies have investigated the application of phage therapy in livestock species as well as companion animals.{{cite journal | vauthors = Ferriol-González C, Domingo-Calap P | title = Phage Therapy in Livestock and Companion Animals | journal = Antibiotics | volume = 10 | issue = 5 | pages = 559 | date = May 2021 | pmid = 34064754 | pmc = 8150778 | doi = 10.3390/antibiotics10050559 | doi-access = free }} Brigham Young University has been researching the use of phage therapy to treat American foulbrood in honeybees.{{cite web |url=https://universe.byu.edu/2016/05/06/byus-bee-team-successfully-treats-honeybee-loss1/ |title=BYU's bee team successfully treats honeybee loss |vauthors=Stolworthy L |date=6 May 2016 |access-date=24 September 2018 |archive-date=26 August 2023 |archive-url=https://web.archive.org/web/20230826150836/https://universe.byu.edu/2016/05/06/byus-bee-team-successfully-treats-honeybee-loss1/ |url-status=live }} Phage therapy is also being investigated for potential applications in aquaculture.{{cite journal | vauthors = Richards GP | title = Bacteriophage remediation of bacterial pathogens in aquaculture: a review of the technology | journal = Bacteriophage | volume = 4 | issue = 4 | pages = e975540 | year = 2014 | pmid = 26713223 | pmc = 4590005 | doi = 10.4161/21597081.2014.975540 }}

Phage therapy has been studied for bacterial spot of stonefruit, caused by Xanthomonas pruni (syn. X. campestris pv. pruni, syn. X. arboricola pv. pruni) in prunus species.{{cite journal | vauthors = Nagy J, Király L, Schwarczinger I | title=Phage therapy for plant disease control with a focus on fire blight | journal=Central European Journal of Biology | publisher=Versita | volume=7 | issue=1 | date=25 December 2011 | issn=2391-5412 | doi=10.2478/s11535-011-0093-x | pages=1–12| s2cid=15484075 | doi-access=free }} Some treatments have been very successful.

The 1925 novel and 1926 Pulitzer Prize winner Arrowsmith by Sinclair Lewis used phage therapy as a plot point.

Greg Bear's 2002 novel Vitals features phage therapy, based on Soviet research, used to transfer genetic material.

The 2012 collection of military history essays about the changing role of women in warfare, Women in War – From Home Front to Front Line includes a chapter featuring phage therapy: "Chapter 17: Women who thawed the Cold War".{{cite web | vauthors = Roberts A | url = https://www.winstonchurchill.org/publications/churchill-bulletin/bulletin-048-jun-2012/churchill-the-wartime-feminist/ | title = Churchill the Wartime Feminist | date = 3 June 2012 | publisher = International Churchill Society (ICS) | access-date = 2 March 2018 | archive-date = 26 August 2023 | archive-url = https://web.archive.org/web/20230826150900/https://winstonchurchill.org/publications/churchill-bulletin/bulletin-048-jun-2012/churchill-the-wartime-feminist/ | url-status = live }}

Steffanie A. Strathdee's book The Perfect Predator: An Epidemiologist's Journey to Save Her Husband from a Deadly Superbug, co-written with her husband, Thomas Patterson, was published by Hachette Book Group in 2019. It describes Strathdee's ultimately successful attempt to introduce phage therapy as a life-saving treatment for her husband, critically ill with a completely antibiotic-resistant Acinetobacter baumannii infection following severe pancreatitis.

{{Portal|Viruses}}

• Antimicrobial resistance
• Paul E. Turner
• Phage display
• Phage monographs
• Prophage

{{Academic peer reviewed|Q100400597|doi-access=free|m|mode=cs1}}

{{reflist|refs=

Abedon ST (2012). Salutary contributions of viruses to medicine and public health. In: Witzany G (ed). Viruses: Essential Agents of Life. Springer. 389–405. {{ISBN|978-94-007-4898-9}}.

{{cite book | vauthors = Brüssow H | date = 2007 | chapter = Phage Therapy: The Western Perspective | veditors = McGrath S, van Sinderen D | title = Bacteriophage: Genetics and Molecular Biology | publisher = Caister Academic Press | location = Norfolk, UK | isbn = 978-1-904455-14-1 }}

{{cite journal | vauthors = Brüssow H | title = Phage therapy: the Escherichia coli experience | journal = Microbiology | volume = 151 | issue = Pt 7 | pages = 2133–2140 | date = July 2005 | pmid = 16000704 | doi = 10.1099/mic.0.27849-0 | doi-access = free }}

{{cite web | url = http://news.byu.edu/archive14-oct-bees.aspx | title = Using microscopic bugs to save the bees | publisher = news.byu.edu | access-date = 1 December 2014 | date = 20 July 2018 | archive-url = https://web.archive.org/web/20141111081929/http://news.byu.edu/archive14-oct-bees.aspx | archive-date = 11 November 2014 | url-status = dead }}

{{cite book | vauthors = Chanishvili N | title = Literature review of the practical application of bacteriophage research. | publisher = Nova Science Publishers, Inc. | date = 2012| page = 184 | isbn = 978-1-62100-851-4 }}

{{cite web | vauthors = Zimmer C | url = http://blogs.discovermagazine.com/loom/2011/05/20/eaters-of-bacteria-is-phage-therapy-ready-for-the-big-time/#.UWhfQ3D0jPs | archive-url = https://web.archive.org/web/20131222034617/http://blogs.discovermagazine.com/loom/2011/05/20/eaters-of-bacteria-is-phage-therapy-ready-for-the-big-time/#.UrZgly_P1qZ | archive-date = 22 December 2013 | title = Eaters of bacteria: Is phage therapy ready for the big time? | publisher = Discover Magazine | access-date = 12 April 2013 | date = 20 May 2011 }}

{{Citation | date = December 2013 | title = December 2013 Faculty Spotlight | publisher = Evergreen College | place = Olympia, WA | url = http://evergreen.edu/faculty/spotlight/dec2013spotlight.htm | access-date = 1 March 2015 | archive-date = 15 September 2016 | archive-url = https://web.archive.org/web/20160915172615/http://evergreen.edu/faculty/spotlight/dec2013spotlight.htm | url-status = dead }}

{{cite web|url=http://www.evergreen.edu/phage/phagetherapy/phagetherapy.htm|title=Phage Therapy: Bacteriophages as Antibiotics |url-status=dead|archive-url=https://web.archive.org/web/20070302111359/http://www.evergreen.edu/phage/phagetherapy/phagetherapy.htm|archive-date=2 March 2007|publisher=Evergreen}}

{{Citation | vauthors = Faltys D | date = 4 August 2013 | title = Evergreen Researcher Dr. Kutter Announces 'There's a Phage for That' | journal = Thurston Talk | place = Olympia, Washington | url = http://www.thurstontalk.com/2013/08/04/evergreen-researcher-dr-kutter-announces-theres-a-phage-for-that | access-date = 1 March 2015 | archive-date = 5 March 2016 | archive-url = https://web.archive.org/web/20160305165852/http://www.thurstontalk.com/2013/08/04/evergreen-researcher-dr-kutter-announces-theres-a-phage-for-that/ | url-status = live }}

{{cite book | vauthors = Fox SI | title = Human Physiology | edition = 6th | publisher = McGraw-Hill | year = 1999 | pages = 50, 55, 448, 449 | url = http://www.mhhe.com/ | isbn = 978-0-697-34191-4 | access-date = 15 December 2007 | archive-date = 26 November 2015 | archive-url = https://web.archive.org/web/20151126022930/http://www.mhhe.com/ | url-status = live }}

{{cite book | vauthors = Hatfull GF | chapter = Mycobacteriophages: Pathogenesis and Applications | pages = 238–255 | veditors = Waldor MK, Friedman DI, Adhya SL | title = Phages: Their role in bacterial pathogenesis and biotechnology | date = 2005 | publisher = ASM Press }}

{{cite book | vauthors = Häusler T | year = 2006 | title = Virus vs. Superbug: A solution to the antibiotic crisis? | publisher = Macmillan | page = 48 | isbn = 978-0-230-55193-0 | chapter = At the limits of medicine; The wild pioneer era }}

{{cite web | work = BBC Horizon | title = Phage – The Virus that Cures | date = 9 October 1997 | url = https://archive.org/details/BBCHorizonS1997e13TheVirusThatCures }}

{{cite web | date = 16 June 2011 | access-date = 4 June 2012 | title = KERA Think! Podcast: Viruses are Everywhere! | url = http://www.kera.org/2011/06/16/viruses-are-everywhere/ | archive-date = 9 October 2016 | archive-url = https://web.archive.org/web/20161009063103/http://www.kera.org/2011/06/16/viruses-are-everywhere/ | url-status = live }} (audio)

{{cite web | vauthors = Kohn D | date = 9 April 2003 |url=https://www.cbsnews.com/news/silent-killers-fantastic-phages/ | archive-url = https://web.archive.org/web/20100703010848/http://www.cbsnews.com/stories/2002/09/19/48hours/main522596.shtml | archive-date = 3 July 2010 |title=Silent Killers: Fantastic Phages?| url-status = live |website=CBS News}}

{{cite book | vauthors = Kuchment A |title=The Forgotten Cure: The Past and Future of Phage Therapy |date=2011 |publisher=Springer |location=New York |isbn=978-1-4614-0250-3 }}{{rp|94}}

{{cite book | vauthors = Kuchment A |title=The Forgotten Cure: The Past and Future of Phage Therapy |date=2011 |publisher=Springer |location=New York |isbn=978-1-4614-0250-3 | page = 94 | quote = [T]he Hirszfeld Institute [in Poland] has almost always done its research studies in the absence of double-bind controls ... . But the sheer quantity of cases, combined with the fact that nearly all the cases involve patients who failed to respond to antibiotics, is persuasive. }}

{{cite book | vauthors = Kuchment A |title=The Forgotten Cure: The Past and Future of Phage Therapy |date=2011 |publisher=Springer |location=New York |isbn=978-1-4614-0250-3| pages = 115–118 | quote = In addition to mentioning that Texas law allows physicians to use "natural substances" like phages in addition to (but not in lieu of) standard medical practice, Kuichment says, "In June 2009 [Dr. Randall Wolcott's] study was published in the Journal of Wound Care. }}

{{cite journal | vauthors = Kutter E, De Vos D, Gvasalia G, Alavidze Z, Gogokhia L, Kuhl S, Abedon ST | title = Phage therapy in clinical practice: treatment of human infections | journal = Current Pharmaceutical Biotechnology | volume = 11 | issue = 1 | pages = 69–86 | date = January 2010 | pmid = 20214609 | doi = 10.2174/138920110790725401 }}

{{cite news | vauthors = Aguita M | title = Combatting Bacterial Infection | publisher = LabNews.co.uk | url = http://www.labnews.co.uk/printer_friendly.php/2912/combating-bacterial-infection | access-date = 5 May 2009 | url-status = dead | archive-url = https://web.archive.org/web/20090228204258/http://www.labnews.co.uk/printer_friendly.php/2912/combating-bacterial-infection | archive-date = 28 February 2009}}

{{Cite web|url=https://www.caister.com/highveld/virology/phage.html|title=The New Phage Biology: From Genomics to Applications|website=www.caister.com|access-date=29 December 2019|archive-date=26 November 2020|archive-url=https://web.archive.org/web/20201126231811/https://www.caister.com/highveld/virology/phage.html|url-status=live}}

{{cite book | veditors = Mc Grath S, Sinderen D | title = Bacteriophage: Genetics and Molecular Biology | edition = 1st | publisher = Caister Academic Press | year = 2007 | url = http://www.horizonpress.com/phage | id = [http://www.horizonpress.com/phage] | isbn = 978-1-904455-14-1 | access-date = 19 September 2007 | archive-date = 22 October 2016 | archive-url = https://web.archive.org/web/20161022062019/http://www.horizonpress.com/phage | url-status = live }}

{{cite news|url=https://www.npr.org/templates/story/story.php?storyId=101547330|title=Scientists Engineer Viruses To Battle Bacteria|newspaper=NPR.org|access-date=2 April 2018|archive-date=4 November 2019|archive-url=https://web.archive.org/web/20191104122645/https://www.npr.org/templates/story/story.php?storyId=101547330|url-status=live}}

{{cite journal | vauthors = Keen EC | title = Phage therapy: concept to cure | journal = Frontiers in Microbiology | volume = 3 | pages = 238 | year = 2012 | pmid = 22833738 | pmc = 3400130 | doi = 10.3389/fmicb.2012.00238 | doi-access = free }}

{{cite magazine | url = http://www.time.com/time/magazine/article/0,9171,847952,00.html | archive-url = https://web.archive.org/web/20090413221820/http://www.time.com/time/magazine/article/0,9171,847952,00.html | url-status = dead | archive-date = 13 April 2009 | title = Phage Findings | access-date = 13 December 2007 | magazine = Time | date = 3 January 1938 }}

{{cite web | url = http://www.phagetherapycenter.com/pii/PatientServlet?command=static_phagetherapy&language=0 | title = What is Phage Therapy? | publisher = phagetherapycenter.com | access-date = 29 November 2014 | archive-date = 21 March 2019 | archive-url = https://web.archive.org/web/20190321111711/http://www.phagetherapycenter.com/pii/PatientServlet?command=static_phagetherapy&language=0 | url-status = live }}

{{cite journal | vauthors = Summers WC | title = Bacteriophage therapy | journal = Annual Review of Microbiology | volume = 55 | pages = 437–451 | year = 2001 | pmid = 11544363 | doi = 10.1146/annurev.micro.55.1.437 }}

{{cite journal | vauthors = Duckworth DH, Gulig PA | title = Bacteriophages: potential treatment for bacterial infections | journal = BioDrugs | volume = 16 | issue = 1 | pages = 57–62 | year = 2002 | pmid = 11909002 | doi = 10.2165/00063030-200216010-00006 | s2cid = 249919919 }}

{{cite journal | vauthors = Shasha SM, Sharon N, Inbar M | title = [Bacteriophages as antibacterial agents] | language = he | journal = Harefuah | volume = 143 | issue = 2 | pages = 121–125, 166 | date = February 2004 | pmid = 15143702 }}

{{cite journal | vauthors = Parfitt T | title = Georgia: an unlikely stronghold for bacteriophage therapy | journal = Lancet | volume = 365 | issue = 9478 | pages = 2166–2167 | year = 2005 | pmid = 15986542 | doi = 10.1016/S0140-6736(05)66759-1 | s2cid = 28089251 }}

{{cite journal | vauthors = Borysowski J, Weber-Dabrowska B, Górski A | title = Bacteriophage endolysins as a novel class of antibacterial agents | journal = Experimental Biology and Medicine | volume = 231 | issue = 4 | pages = 366–377 | date = April 2006 | pmid = 16565432 | doi = 10.1177/153537020623100402 | s2cid = 28367348 }}

{{cite journal | vauthors = Yacoby I, Shamis M, Bar H, Shabat D, Benhar I | title = Targeting antibacterial agents by using drug-carrying filamentous bacteriophages | journal = Antimicrobial Agents and Chemotherapy | volume = 50 | issue = 6 | pages = 2087–2097 | date = June 2006 | pmid = 16723570 | pmc = 1479106 | doi = 10.1128/AAC.00169-06 }}

{{cite journal | vauthors = McVay CS, Velásquez M, Fralick JA | title = Phage therapy of Pseudomonas aeruginosa infection in a mouse burn wound model | journal = Antimicrobial Agents and Chemotherapy | volume = 51 | issue = 6 | pages = 1934–1938 | date = June 2007 | pmid = 17387151 | pmc = 1891379 | doi = 10.1128/AAC.01028-06 }}

{{cite journal | vauthors = Yacoby I, Bar H, Benhar I | title = Targeted drug-carrying bacteriophages as antibacterial nanomedicines | journal = Antimicrobial Agents and Chemotherapy | volume = 51 | issue = 6 | pages = 2156–2163 | date = June 2007 | pmid = 17404004 | pmc = 1891362 | doi = 10.1128/AAC.00163-07 }}

{{cite journal | vauthors = Hanlon GW | title = Bacteriophages: an appraisal of their role in the treatment of bacterial infections | journal = International Journal of Antimicrobial Agents | volume = 30 | issue = 2 | pages = 118–128 | date = August 2007 | pmid = 17566713 | doi = 10.1016/j.ijantimicag.2007.04.006 }}

{{cite journal | vauthors = Verbeken G, De Vos D, Vaneechoutte M, Merabishvili M, Zizi M, Pirnay JP | title = European regulatory conundrum of phage therapy | journal = Future Microbiology | volume = 2 | issue = 5 | pages = 485–491 | date = October 2007 | pmid = 17927471 | doi = 10.2217/17460913.2.5.485 }}

{{cite journal | vauthors = Mangen MJ, Havelaar AH, Poppe KP, de Wit GA | title = Cost-utility analysis to control Campylobacter on chicken meat: dealing with data limitations | journal = Risk Analysis | volume = 27 | issue = 4 | pages = 815–830 | date = August 2007 | pmid = 17958494 | doi = 10.1111/j.1539-6924.2007.00925.x | author5 = CARMA Project Team | bibcode = 2007RiskA..27..815M | s2cid = 25966489 }}

{{cite journal | vauthors = Bar H, Yacoby I, Benhar I | title = Killing cancer cells by targeted drug-carrying phage nanomedicines | journal = BMC Biotechnology | volume = 8 | pages = 37 | date = April 2008 | pmid = 18387177 | pmc = 2323368 | doi = 10.1186/1472-6750-8-37 | doi-access = free }}

{{cite journal | vauthors = Summers WC | title = On the origins of the science in Arrowsmith: Paul de Kruif, Felix d'Herelle, and phage | journal = Journal of the History of Medicine and Allied Sciences | volume = 46 | issue = 3 | pages = 315–332 | date = July 1991 | pmid = 1918921 | doi = 10.1093/jhmas/46.3.315 }}

{{cite journal | vauthors = Górski A, Miedzybrodzki R, Borysowski J, Weber-Dabrowska B, Lobocka M, Fortuna W, Letkiewicz S, Zimecki M, Filby G | display-authors = 6 | title = Bacteriophage therapy for the treatment of infections | journal = Current Opinion in Investigational Drugs | volume = 10 | issue = 8 | pages = 766–774 | date = August 2009 | pmid = 19649921 }}

{{cite journal | vauthors = Soothill JS | title = Bacteriophage prevents destruction of skin grafts by Pseudomonas aeruginosa | journal = Burns | volume = 20 | issue = 3 | pages = 209–211 | date = June 1994 | pmid = 8054131 | doi = 10.1016/0305-4179(94)90184-8 }}

{{cite journal | vauthors = Rhoads DD, Wolcott RD, Kuskowski MA, Wolcott BM, Ward LS, Sulakvelidze A | title = Bacteriophage therapy of venous leg ulcers in humans: results of a phase I safety trial | journal = Journal of Wound Care | volume = 18 | issue = 6 | pages = 237–238, 240–243 | date = June 2009 | pmid = 19661847 | doi = 10.12968/jowc.2009.18.6.42801 }}

{{cite journal | vauthors = Stone R | title = Bacteriophage therapy. Stalin's forgotten cure | journal = Science | volume = 298 | issue = 5594 | pages = 728–731 | date = October 2002 | pmid = 12399562 | doi = 10.1126/science.298.5594.728 | url = http://www.phage-biotech.com/images/Science-phagetherapy.pdf | access-date = 18 November 2007 | url-status = dead | s2cid = 22395770 | archive-url = https://web.archive.org/web/20160625234600/http://www.phage-biotech.com/images/Science-phagetherapy.pdf | archive-date = 25 June 2016 }}

{{cite book | vauthors = Lewis S | chapter-url = http://www.sparknotes.com/lit/arrowsmith/section11.rhtml | title = SparkNotes | publisher = Arrowsmith | chapter = Chapters 31–33 | access-date = 13 December 2007 | archive-date = 8 October 2017 | archive-url = https://web.archive.org/web/20171008220129/http://www.sparknotes.com/lit/arrowsmith/section11.rhtml | url-status = live }}

{{cite journal | vauthors = Thiel K | title = Old dogma, new tricks – 21st Century phage therapy | journal = Nature Biotechnology | volume = 22 | issue = 1 | pages = 31–36 | date = January 2004 | pmid = 14704699 | doi = 10.1038/nbt0104-31 | s2cid = 27108321 }}

{{cite web | url = http://www.biocontrol.ltd.uk/STVdoc.htm | title = Sourcing Development Funding: Biocontrol | work = biocontrol.ltd.uk | access-date = 13 December 2007 | url-status = dead | archive-url = https://web.archive.org/web/20090415093442/http://www.biocontrol.ltd.uk/STVdoc.htm | archive-date = 15 April 2009}}

{{cite web | url = http://www.biocontrol-ltd.com/PressNews/tabid/61/articleType/ArticleView/articleId/9/Scientists-start-germ-warfare-to-beat-illness.aspx | title = Scientists start germ warfare to beat illness. | work = biocontrol-ltd.com | access-date = 30 April 2008 | url-status = dead | archive-url = https://web.archive.org/web/20080526025446/http://www.biocontrol-ltd.com/PressNews/tabid/61/articleType/ArticleView/articleId/9/Scientists-start-germ-warfare-to-beat-illness.aspx | archive-date = 26 May 2008}}

{{cite web | url = http://www.bccapital.co.uk/PressNews/tabid/118/Default.aspx | title = Press & News | access-date = 13 December 2007 | url-status = dead | archive-url = https://web.archive.org/web/20071130182004/http://www.bccapital.co.uk/PressNews/tabid/118/Default.aspx | archive-date = 30 November 2007}}

{{cite journal | vauthors = Wright A, Hawkins CH, Anggård EE, Harper DR | title = A controlled clinical trial of a therapeutic bacteriophage preparation in chronic otitis due to antibiotic-resistant Pseudomonas aeruginosa; a preliminary report of efficacy | journal = Clinical Otolaryngology | volume = 34 | issue = 4 | pages = 349–357 | date = August 2009 | pmid = 19673983 | doi = 10.1111/j.1749-4486.2009.01973.x | doi-access = free }}

{{cite web | url = https://www.youtube.com/watch?v=rj9_QGBJN0w | title = Bee Killers: Using Phages Against Deadly Honeybee Diseases | date = 27 October 2014 | publisher = youtube.com | access-date = 29 November 2014 | archive-date = 7 January 2021 | archive-url = https://web.archive.org/web/20210107173948/https://www.youtube.com/watch?v=rj9_QGBJN0w | url-status = live }}

}}

{{refbegin}}

• {{cite book | vauthors = Kulkarni K | year = 2014 | title = The Forgotten Cure: The Past and Future of Phage Therapy | publisher = Science India | isbn = 978-1-4614-0250-3 |ref=none}}
• {{cite journal | vauthors = Thiel K | title = Old dogma, new tricks–21st Century phage therapy | journal = Nature Biotechnology | volume = 22 | issue = 1 | pages = 31–36 | date = January 2004 | pmid = 14704699 | doi = 10.1038/nbt0104-31 | s2cid = 27108321 }}

{{refend}}

• [https://www.youtube.com/watch?v=xvC8xME5Zrg iBiology video: Phage Therapy (2016)]
• [http://www.popsci.com/scitech/article/2009-03/next-phage?page=1 Popular Science – "The Next Phage" (2009)]

{{Concepts in infectious disease}}

Category:Bacteriophages

Category:Therapy

Category:Health in the Soviet Union