Comparison between American and European legislation in the therapeutical and alimentary bacteriophage usage

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Zakira Naureen
Daniele Malacarne
Kyrylo Anpilogov
Astrit Dautaj
Giorgio Camilleri
Stefano Cecchin
Simone Bressan
Arianna Casadei
Elena Albion
Elisa Sorrentino
Tommaso Beccari
Munis Dundar
Matteo Bertelli


Bacteriophages, antimicrobial resistance, regulatory issues, applications of phages


Bacteriophages, though discovered a century ago, still lag behind in the race of antimicrobials due to scarce information about their biology, pharmacology, safety and suitability as therapeutic agents. Although they possess several capabilities of practical utility in medicine, they are still unable to satisfy the regulatory standards set by the regulatory authorities in both United States (US) and European Union (EU). Bacteriophages and their products (lysins) are considered as drugs, therefore they should follow the same route of the chemical drugs in order to achieve regulatory approvals for commercial production and application. However, lack of definitive guidelines and regulations has rendered bacteriophages less attractive to pharmaceutical companies and funding agencies, making it difficult for clinicians and researchers to set up wide scale clinical trials in order to prove efficacy, safety and stability of bacteriophages and their products. In this review, we will discuss the current regulations for developing phages and phage-based products for therapeutic purposes in the US and EU.


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1. Hankin EH. L’action bactéricide des eaux de la Jumna et du Gange sur le vibrion du choléra. Ann Inst Pasteur (Paris) 1896; 10: 511–23.
2. Twort FW. An investigation on the nature of ultra-microscopic viruses. Lancet 1915; 186: 1241–3.
3. Keen EC. Phage therapy: concept to cure. Front Microbiol 2012; 3: 238.
4. d’Herelle F. Sur un microbe invisible antagoniste des bacilles dysentériques. Comptes Rendus Acad Sci Paris 1917; 165: 173–5.
5. d’Herelle F. Bacteriophage as a treatment in acute medical and surgical infections. Bull N Y Acad Med 1931; 7: 329–348.
6. Fleming A. On the antibacterial action of cultures of a Penicillium with special reference to their use in the isolation of B. influenza. Br J Exp Pathol 1929; 10: 226–36.
7. Chain E, Florey HW, Gardner NG, et al. Penicillin as a chemotherapeutic agent. Lancet 1940; 236: 226–8.
8. WHO. 2018. Antimicrobial resistance WHO.‐room/fact‐sheets/detail/antimicrobial‐resistance.
9. WHO. 2017. Global priority list of antibiotic‐resistant bacteria to guide research, discovery, and development of new antibiotics.‐priority‐list‐antibiotic‐resistant‐bacteria/en/.
10. Luepke KH, Suda KJ, Boucher H, et al. Past, present, and future of antibacterial economics: increasing bacterial resistance, limited antibiotic pipeline, and societal implications. Pharmacotherapy 2017; 37: 71–84.
11. Tacconelli E, Carrara E, Savoldi A, et al. WHO Pathogens Priority List Working Group. Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic‐resistant bacteria and tuberculosis. Lancet Infect Dis 2018; 18(3): 318‐27.
12. United Nations. 2017. PRESS RELEASE: High-Level Meeting on Antimicrobial Resistance. 2016; Accessed Mar 29, 2017.
13. Nair RR, Vasse M, Wielgoss S, et al. Bacterial predator-prey coevolution accelerates genome evolution and selects on virulence-associated prey defences. Nat Commun 2019; 10: 4301.
14. Simmonds P, Aiewsakun P. Virus classification — where do you draw the line? Arch Virol 2018; 163: 2037–46.
15. European Commission. Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community Code Relating to Medicinal Products for Human Use (consolidated version: 16/11/2012). In EudraLex—The Rules Governing Medicinal Products in the European Union (Volume 1), Pharmaceutical Legislation: Medicinal Products For Human Use. Availableonline: Commission Directive 2003/63/EC of 25 June 2003 amending.
16. Directive 2001/83/EC of the European Parliament and the council of the Community code relating to medicinal products for human use. Official Journal of the European Union.
17. Verbeken G, Pirnay JP, De Vos D, et al. (2012) Optimizing the European regulatory framework for sustainable bacteriophage therapy in human medicine. Arch Immunol Ther Exp (Warsz) 2012; 60: 161–72.
18. European Medicines Agency (EMA). Workshop on the Therapeutic Use of Bacteriophages. 2015. Available online:
19. Guo Z, Lin H, Ji X, et al. Therapeutic applications of lytic phages in human medicine. Microb Pathog 2020; 142:04048.
20. Verbeken G, De Vos D, Vaneechoutte M, Merabishvili M, Zizi M, Pirnay JP. European regulatory conundrum of phage therapy. Future Microbiol 2007; 2(5): 485-91.
21. Colavecchio A, Cadieux B, Lo A, Goodridge LD. Bacteriophages contribute to the spread of antibiotic resistance genes among foodborne pathogens of the enterobacteriaceae family – A review. Front Microbiol 2017; 8: 1108.
22. Pirnay JP, De Vos D, Verbeken G, et al. The phage therapy paradigm: prêt-à-porter or surmesure? Pharm Res 2011; 28: 934–7.
23. Moelling K, Broecker F, Willy C. A wake-up call: We need phage therapy now. Viruses 2018; 10: 688.
24. Bourdin G, Schmitt B, Marvin Guy L, et al. Amplification and purification of T4-like Escherichia coli phages for phage therapy: From laboratory to pilot scale. Appl Environ Microbiol 2014; 80: 1469–76.
25. Anomaly J. The future of phage: Ethical challenges of using phage therapy to treat bacterial infections, Public Health Ethics 2020; 13 (1): 82–8.
26. Rohde C, Wittmann J, Kutter E. Bacteriophages: A therapy concept against multi-drug-resistant bacteria. Surg Infect (Larchmt) 2018; 19: 737–44.
27. Sybesma W, Rohde C, Bardy P, et al. Silk Route to the acceptance and re-implementation of bacteriophage therapy-Part II. Antibiotics 2018; 7: 35.
28. Abedon ST. Lysis from without. Bacteriophage 2011; 1: 46-9.
29. Loc-Carrillo C, Abedon S. Pros and cons of phage therapy. Bacteriophage 2011; 1: 111–4.
30. Brives C, Pourraz J. Phage therapy as a potential solution in the fight against AMR: obstacles and possible futures. Palgrave Commun 2020; 6: 100.
31. Koskella B, Brockhurst MA. Bacteria-phage coevolution as a driver of ecological and evolutionary processes in microbial communities. FEMS Microbiology Rev 2014; 38: 916–31.
32. Maciejewska B, Olszak T, Drulis-Kawa Z. Applications of bacteriophages versus phage enzymes to combat and cure bacterial infections: an ambitious and also a realistic application? Appl Microbiol Biotechnol 2018; 102(6): 2563–81.
33. Brüssow H. What is needed for phage therapy to become a reality in Western medicine? Virology 2012; 434: 138-42.
34. Pirnay JP, Verbeken G, Rose T, et al. Introducing yesterday’s phage therapy in today’s medicine. Future Virol 2012; 7: 379-90.
35. Patey O, McCallin S, Mazure H, Liddle M, Smithyman A, Dublanchet A. Clinical indications and compassionate use of phage therapy: personal experience and literature review with a focus on osteoarticular infections. Viruses 2019; 11: 18.
36. Pirnay JP, Verbeken G, Ceyssens PJ, et al. The magistral phage. Viruses 2018; 10(2): 64.
37. Djebara S, Maussen C, De Vos D, et al. Processing phage therapy requests in a Brussels military hospital: lessons identified. Viruses 2019; 11: 265.
38. Gorski A, Jonczyk-Matysiak E, LusiakSzelachowska M, et al. The potential of phage therapy in sepsis. Front Immunol 2017; 8: 1783.
39. Kasman LM, Kasman A, Westwater C, Dolan J, Schmidt MG, Norris JS. Overcoming the phage replication threshold: a mathematical model with implications for phage therapy. J Virol 2002; 76: 5557-64.
40. Dedrick RM, Guerrero-Bustamante CA, Garlena RA, et al. Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus. Nat Med 2019; 25: 730–3.
41. Dvořáčková M, Růžička F, Benešík M, et al. Antimicrobial effect of commercial phage preparation Stafal® on biofilm and planktonic forms of methicillin-resistant Staphylococcus aureus. Folia Microbiol 2019; 64: 121–6.
42. Miedzybrodzki R, Borysowski J, Weber-Dabrowska B, et al. Clinical aspects of phage therapy. Adv Virus Res 2012; 83: 73–121.
43. Jennes S, Merabishvili M, Soentjens P, et al. Use of bacteriophages in the treatment of colistin-only-sensitive Pseudomonas aeruginosa septicaemia in a patient with acute kidney injury—a case report. Crit Care 2017; 21: 129.
44. Poole K. Pseudomonas aeruginosa: Resistance to the max. Front Microbiol 2011; 2: 65.
45. PhagoMed. Available online:
46. Geförderte Projekte des Innovationsausschusses zur Förderbekanntmachung Versorgungsforschung vom 20.Oktober 2017, PhagoFlow (page 25). Available online:
47. Ujmajuridze A, Chanishvili N, Goderdzishvili M, et al. Adapted bacteriophages for treating urinary tract infections. Front Microbiol 2018; 9: 1832.
48. UCSD. Center for innovative phage applications and therapeutics.‐innovative‐phage‐applications‐and‐therapeutics/Pages/default.aspx. Accessed January 14, 2019.

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