Editing Bacteriophage (section)

=== Phage therapy ===
{{Main|Phage therapy}}

[[File:George Eliava 1892–1937.jpg|right|thumb|upright|[[George Eliava]] pioneered the use of phages in treating bacterial infections]]

Phages were discovered to be antibacterial agents and were used in the former [[Soviet]] Republic of [[Georgia (country)|Georgia]] (pioneered there by [[Giorgi Eliava]] with help from the co-discoverer of bacteriophages, [[Félix d'Hérelle]]) during the 1920s and 1930s for treating bacterial infections.

D'Herelle "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."<ref>{{Citation | vauthors = Kuchment A | year = 2012 | title = The Forgotten Cure: The past and future of phage therapy | publisher = Springer | page  = 11 | isbn = 978-1-4614-0250-3 }}</ref>

They had widespread use, including treatment of soldiers in the [[Red Army]].<ref>{{cite journal | vauthors = Myelnikov D | title = An Alternative Cure: The Adoption and Survival of Bacteriophage Therapy in the USSR, 1922-1955 | journal = Journal of the History of Medicine and Allied Sciences | volume = 73 | issue = 4 | pages = 385–411 | date = October 2018 | pmid = 30312428 | pmc = 6203130 | doi = 10.1093/jhmas/jry024 }}</ref> However, they were abandoned for general use in the West for several reasons:
* Antibiotics were discovered and marketed widely. They were easier to make, store, and prescribe.
* Medical trials of phages were carried out, but a basic lack of understanding of phages raised questions about the validity of these trials.<ref>{{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 | s2cid = 31626252 }}</ref>
* Publication of research in the Soviet Union was mainly in the [[Russian language|Russian]] or [[Georgian language]]s and for many years was not followed internationally.
* The Soviet technology was widely discouraged and in some cases illegal due to the [[red scare]].

The use of phages has continued since the end of the [[Cold War]] in Russia,<ref name="Gol">{{cite journal | vauthors = Golovin S | url = https://www.nkj.ru/archive/articles/31498/ | title = Бактериофаги: убийцы в роли спасителей | trans-title = Bacteriophages: killers as saviors | language = Russian | journal = [[Наука и жизнь]] | trans-journal = Nauka I Zhizn (Science and life) | date = 2017 | issue = 6 | pages = 26–33 }}</ref> Georgia, and elsewhere in Central and Eastern Europe. The first regulated, randomized, double-blind [[clinical trial]] was reported in the ''Journal of Wound Care'' in June 2009, which evaluated the safety and efficacy of a bacteriophage cocktail to treat infected venous ulcers of the leg in human patients.<ref name="Rhoads2009">{{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 = 237–8, 240–3 | date = June 2009 | pmid = 19661847 | doi = 10.12968/jowc.2009.18.6.42801 }}</ref> The FDA approved the study as a Phase I clinical trial. The study's results demonstrated the safety of therapeutic application of bacteriophages, but did not show efficacy. The authors explained that the use of certain chemicals that are part of standard wound care (e.g. [[lactoferrin]] or silver) may have interfered with bacteriophage viability.<ref name="Rhoads2009" /> Shortly after that, another controlled clinical trial in Western Europe (treatment of ear infections caused by ''Pseudomonas aeruginosa'') was reported in the journal ''[[Clinical Otolaryngology]]'' in August 2009.<ref name="Wright2009">{{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 }}</ref> The study concludes that bacteriophage preparations were safe and effective for treatment of chronic ear infections in humans. Additionally, there have been numerous animal and other experimental clinical trials evaluating the efficacy of bacteriophages for various diseases, such as infected burns and wounds, and cystic fibrosis-associated lung infections, among others.<ref name="Wright2009"/> On the other hand, phages of ''[[Inoviridae]]'' have been shown to complicate [[biofilms]] involved in [[pneumonia]] and [[cystic fibrosis]] and to shelter the bacteria from drugs meant to eradicate disease, thus promoting persistent infection.<ref>{{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 | 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 | doi-access = free }}</ref>

Meanwhile, bacteriophage researchers have been developing engineered viruses to overcome [[antimicrobial resistance|antibiotic resistance]], and engineering the phage genes responsible for coding enzymes that degrade the biofilm matrix, phage structural proteins, and the enzymes responsible for [[lysis]] of the bacterial cell wall.<ref name="mmbr"/><ref name="Prescott"/><ref name="horizon"/> There have been results showing that T4 phages that are small in size and short-tailed can be helpful in detecting ''E. coli'' in the human body.<ref>{{cite journal | vauthors = Tawil N, Sacher E, Mandeville R, Meunier M | title = Surface plasmon resonance detection of E. coli and methicillin-resistant S. aureus using bacteriophages | journal = Biosensors & Bioelectronics | volume = 37 | issue = 1 | pages = 24–29 | date = May 2012 | pmid = 22609555 | doi = 10.1016/j.bios.2012.04.048 | url = https://lp2l.polymtl.ca/sites/default/files/Articles/2012-Tawil.pdf | url-status = live | archive-url = https://web.archive.org/web/20230202231339/https://lp2l.polymtl.ca/sites/default/files/Articles/2012-Tawil.pdf | archive-date = 2023-02-02 }}</ref>

Therapeutic efficacy of a phage cocktail was evaluated in a mouse model with nasal infection of multi-drug-resistant (MDR) ''[[A. baumannii]]''. Mice treated with the phage cocktail showed a 2.3-fold higher survival rate compared to those untreated at seven days post-infection.<ref>{{cite journal | vauthors = Cha K, Oh HK, Jang JY, Jo Y, Kim WK, Ha GU, Ko KS, Myung H | title = Characterization of Two Novel Bacteriophages Infecting Multidrug-Resistant (MDR) ''Acinetobacter baumannii'' and Evaluation of Their Therapeutic Efficacy ''in Vivo'' | journal = Frontiers in Microbiology | volume = 9 | page = 696 | date = 10 April 2018 | pmid = 29755420 | pmc = 5932359 | doi = 10.3389/fmicb.2018.00696 | doi-access = free }}</ref>

In 2017, a 68-year-old diabetic patient with necrotizing pancreatitis complicated by a pseudocyst infected with MDR ''A. baumannii'' strains was being treated with a cocktail of Azithromycin, Rifampicin, and Colistin for 4 months without results and overall rapidly declining health.

Because discussion had begun of the clinical futility of further treatment, an Emergency Investigational New Drug (eIND) was filed as a last effort to at the very least gain valuable medical data from the situation, and approved, so he was subjected to phage therapy using a percutaneously (PC) injected cocktail containing nine different phages that had been identified as effective against the primary infection strain by rapid isolation and testing techniques (a process which took under a day). This proved effective for a very brief period, although the patient remained unresponsive and his health continued to worsen; soon isolates of a strain of ''A. baumannii'' were being collected from drainage of the cyst that showed resistance to this cocktail, and a second cocktail which was tested to be effective against this new strain was added, this time by intravenous (IV) injection as it had become clear that the infection was more pervasive than originally thought.<ref name="PhageCockt2017"/>

Once on the combination of the IV and PC therapy the patient's downward clinical trajectory reversed, and within two days he had awoken from his coma and become responsive. As his immune system began to function he had to be temporarily removed from the cocktail because his fever was spiking to over {{convert|104|F|C}}, but after two days the phage cocktails were re-introduced at levels he was able to tolerate. The original three-antibiotic cocktail was replaced by minocycline after the bacterial strain was found not to be resistant to this and he rapidly regained full lucidity, although he was not discharged from the hospital until roughly 145 days after phage therapy began. Towards the end of the therapy it was discovered that the bacteria had become resistant to both of the original phage cocktails, but they were continued because they seemed to be preventing minocycline resistance from developing in the bacterial samples collected so were having a useful synergistic effect.<ref name="PhageCockt2017">{{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 | 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 | date = October 2017 | pmid = 28807909 | pmc = 5610518 | doi = 10.1128/AAC.00954-17 }}</ref>