Therapeutic and Prophylactic Bacteriophage Preparations: Efficacy, Safety, and International Regulatory Experience (Review)

INTRODUCTION. Bacteriophage preparations are effective in bacterial infections, including multi-drug resistant pathogens. In order to develop and widely use standardized and personalized phage therapy, current regulations and guidelines governing the development, clinical trials, registration, and distribution of bacteriophage preparations necessitate an update.

AIM. This study aimed to analyze global trends in the development, registration, as well as efficacy and safety assessment of bacteriophage preparations to identify promising areas for development of phage therapy in the Russian Federation.

DISCUSSION. Despite the proven efficacy, rapidly expanding resistance of pathogens, complicated delivery to the infection focal point, and poorly understood safety of phage therapy prevent wide implementation of bacteriophages in clinical practice. In case standardized bacteriophage preparations show decreased effectiveness, a modified formulation may be warranted, with the updated strains; however, no appropriate legislative mechanisms exist so far. To date, 14 standardized bacteriophage preparations were registered and used in the Russian Federation, with completed clinical trials. Personalized phage therapy is used to a lesser extent. In the United States and the European Union (EU) member states, strict requirements for safety and efficacy evidence are placed; phage therapy is not an official treatment method but is used in individual cases. In some countries, particularly Poland and Belgium, phage therapy is under close supervision, while the use of bacteriophages remains individualized. In 2025, a draft of a concept document stipulating development and production of bacteriophage agents for human use was developed in the EU. However, none of the drugs for phage therapy was approved according to the EU and US requirements.

CONCLUSIONS. Russian Federation has a unique experience of using standardized phage preparations. Regulatory algorithms of modifying the formulation of a registered bacteriophage preparation are still to be developed both in the Russian Federation and other countries. Worldwide harmonization of the regulatory base is an essential element of global development; points to consider include new EU and US initiatives on developing regulatory documents, intensified research aimed at overcoming bacterial resistance to bacteriophages, and long-term safety studies.

1. Żaczek M, Weber-Dąbrowska B, Międzybrodzki R, et al. Phage therapy in Poland — a centennial journey to the first ethically approved treatment facility in Europe. Front Microbiol. 2020;11:1056. https://doi.org/10.3389/fmicb.2020.01056

2. Faltus T. The medicinal phage-regulatory roadmap for phage therapy under EU pharmaceutical legislation. Viruses. 2024;16(3):443. https://doi.org/10.3390/v16030443

3. Verbeken G, Pirnay JP, Lavigne R, et al. Viruses that can cure, when antibiotics fail. J Microb Biochem Technol. 2016;(8):21–4. https://doi.org/10.4172/1948-5948.1000257

4. Pirnay JP, Verbeken G, Ceyssens PJ, et al. The magistral phage. Viruses. 2018;10(2):64. https://doi.org/10.3390/v10020064

5. Pirnay JP, Verbeken G. Magistral phage preparations: Is this the model for everyone? Clin Infect Dis. 2023;77(Suppl 5):S360–9. https://doi.org/10.1093/cid/ciad481

6. Gordillo Altamirano FL, Barr JJ. Phage therapy in the postantibiotic era. Clin Microbiol Rev. 2019;32(2):e00066-18. https://doi.org/10.1128/CMR.00066-18

7. Pendleton JN, Gorman SP, Gilmore BF. Clinical relevance of the ¬ESKAPE pathogens. Expert Rev Anti Infect Ther. 2013;11(3):297–308. https://doi.org/10.1586/eri.13.12

8. Strathdee SA, Hatfull GF, Mutalik VK, Schooley RT. Phage therapy: From biological mechanisms to future directions. Cell. 2023;186(1):17–31. https://doi.org/10.1016/j.cell.2022.11.017

9. Debarbieux L, Pirnay JP, Verbeken G, et al. A bacteriophage journey at the European Medicines Agency. FEMS Microbiol Lett. 2016;363(2):fnv225. https://doi.org/10.1093/femsle/fnv225

10. Abdelkader K, Gerstmans H, Saafan A, et al. The preclinical and clinical progress of bacteriophages and their lytic enzymes: The parts are easier than the whole. Viruses. 2019;11(2):96. https://doi.org/10.3390/v11020096

11. Davydov DS, Parfenyuk RL, Durmanova ZV, et al. Specific aspects of bacteriophage regulation: international practices and future developments. Biological Products. Prevention, Diagnosis, Treatment. 2024;24(3):322–34 (In Russ.). https://doi.org/10.30895/2221-996X-2024-24-3-322-334

12. Davydov DS, Parfenyuk RL, Durmanova ZV, et al. Characteristic aspects of marketing authorisation and quality assurance of bacteriophage medicinal products in the Russian Federation. Biological Products. Prevention, Diagnosis, Treatment. 2023;23(2):181–93 (In Russ.). https://doi.org/10.30895/2221-996X-2023-431

13. Kim MS, Kim YD, Hong SS, et al. Phage-encoded colanic acid-degrading enzyme permits lytic phage infection of a capsule-forming resistant mutant Escherichia coli strain. Appl Environ Microbiol. 2015;81(3):900–9. https://doi.org/10.1128/AEM.02606-14

14. Pires DP, Cleto S, Sillankorva S, et al. Genetically engineered phages: A review of advances over the last decade. Microbiol Mol Biol Rev. 2016;80(3):523–43. https://doi.org/10.1128/mmbr.00069-15

15. Ghatbale P, Blanc A, Sue A, et al. Experimental phage evolution results in expanded host ranges against antibiotic resistant Klebsiella pneumoniae isolates. Nat Commun. 2025;16(1):9903. https://doi.org/10.1038/s41467-025-66062-7

16. Gu Liu C, Green SI, Min L, et al. Phage-antibiotic synergy is driven by a unique combination of antibacterial mechanism of action and stoichiometry. mBio. 2020;11(4):e01462-20. https://doi.org/10.1128/mBio.01462-20

17. Malika DJ, Sokolova IJ, Vinnera GK, et al. Formulation, stabilisation and encapsulation of bacteriophage for phage therapy. Adv Colloid Interface Sci. 2017;249:100–33. https://doi.org/10.1016/j.cis.2017.05.014

18. Jault P, Leclerc T, Jennes S, et al. 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. Lancet. 2019;19(1):35–45. https://doi.org/10.1016/S1473-3099(18)30482-1

19. Huang G, Wei Z, Wang D. What do we lean from the “PhagoBurn” project. Burns. 2019;45(1):260. https://doi.org/10.1016/j.burns.2018.11.008

20. Bakhrushina EO, Anurova MN, Aleshkin AV, et al. Modern tendencies of the use and development of drugs of bacteriophages. Annals of the Russian Academy of Medical Sciences. 2021;76(4):351–60 (In Russ.). https://doi.org/10.15690/vramn1380

21. Górski A, Międzybrodzki R, Węgrzyn G, et al. Phage therapy: Current status and perspectives. Med Res Rev. 2020;40(1):459–63. https://doi.org/10.1002/med.21593

22. Liu D, Van Belleghem JD, de Vries CR, et al. The safety and toxicity of phage therapy: A review of animal and clinical studies. Viruses. 2021;13(7):1268. https://doi.org/10.3390/v13071268

23. Steele A, Stacey HJ, de Soir S, Jones JD. The safety and efficacy of phage therapy for superficial bacterial infections: A systematic review. Antibiotics (Basel). 2020;9(11):754. https://doi.org/10.3390/antibiotics9110754

24. Verbeken G, Pimay JP, Lavigne R, et al. Call for a dedicated european legal framework for bacteriophage therapy. Arch Immunol Ther Exp (Warsz). 2014;62(2):117–29. https://doi.org/10.1007/s00005-014-0269-y

25. Wu N, Chen LK, Zhu T. Phage therapy for secondary bacterial infections with COVID-19. Curr Opin Virol. 2022;52:9–14. https://doi.org/10.1016/j.coviro.2021.11.001

26. Fukaya-Shiba A, Ogata A, Kuribayashi R, et al. Regulatory considerations for developing phage therapy medicinal products for the treatment of antimicrobial resistant bacterial infections. Front Pharmacol. 2025;16:1713471. https://doi.org/10.3389/fphar.2025.1713471

27. Kasurinen J, Spruit CM, Wicklund A, et al. Screening of bacteriophage encoded toxic proteins with a next generation sequencing-based assay. Viruses. 2021;13(5):750. https://doi.org/10.3390/v13050750

28. Uyttebroek S, Chen B, Onsea J, et al. Safety and efficacy of phage therapy in difficult-to-treat infections: a systematic review. Lancet Infect Dis. 2022;22(8):e208–20. https://doi.org/10.1016/s1473-3099(21)00612-5

29. Abedon ST, Thomas-Abedon C. Phage therapy pharmacology. Curr Pharm Biotechnol. 2010;11(1):28–47. https://doi.org/10.2174/138920110790725410

30. 30 Loh B, Gondil VS, Manohar P, et al. Encapsulation and delivery of therapeutic phages. Appl Environ Microbiol. 2021;87(5):e01979–20. https://doi.org/10.1128/aem.01979-20

31. Karn SL, Gangwar M, Kumar R, et al. Phage therapy:A revolutionary shift in the management of bacterial infections, pioneering new horizons in clinical practice, and reimagining the arsenal against microbial pathogens. Front Med. 2023;10:1209782. https://doi.org/10.3389/fmed.2023.1209782

32. Bretaudeau L, Tremblais K, Aubrit F, et al. Good Manufacturing Practice (GMP) compliance for phage therapy medicinal products. Front Microbiol. 2020;11:1161. https://doi.org/10.3389/fmicb.2020.01161

33. Gorski A, Miedzybrodzki R, Weber-Dabrowska B, et al. Phage therapy: Combating infections with potential for evolving from merely a treatment for complications to targeting diseases. Front Microbiol. 2016;7:1515. https://doi.org/10.3389/fmicb.2016.01515

34. 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 (Praha). 2019;64(1):121–6. https://doi.org/10.1007/s12223-018-0622-3

35. Miedzybrodzki R, Fortuna W, Weber-Dabrowska B, Górski A. Phage therapy of staphylococcal infections (including MRSA) may be less expensive than antibiotic treatment. Postepy Hig Med Dosw (Online). 2007;61:461–5. PMID: 17679835

36. Romanovskii GB, Romanovskaya EA, Dasaeva AI. Public law regulation in the field of biomedicine in the Republic of Poland. Current Issues of the State and Law. 2025;9(2):226–35 (In Russ.). https://doi.org/10.20310/2587-9340-2025-9-2-226-235

37. Zaczek, M, Górski A, Weber-Dabrowska B, et al. Thorough synthesis of phage therapy unit activity in Poland — Its history, milestones and international recognition. Viruses. 2022;14:1170. https://doi.org/10.3390/v14061170

38. Eskenazi A, Lood C, Wubbolts J, et al. Combination of pre-adapted bacteriophage therapy and antibiotics for treatment of fracture-¬related infection due to pandrug-resistant Klebsiella pneumonia. Nat Commun. 2022;13(1):302. https://doi.org/10.1038/s41467-021-27656-z

39. Farrell AT, Goldberg KB, Pazdur R. Flexibility and innovation in the FDA’s novel regulatory approval strategies for hematologic drug. Blood. 2017;130(11):1285–9. https://doi.org/10.1182/blood-2017-04-742726

40. Landyshev NN, Voronko YaG, Timoshina OYu. A review of the regu¬latory framework for personalized bacteriophages registration. Problems of Virology. 2020;65(5):259–66 (In Russ.). https://doi.org/10.36233/0507-4088-2020-65-5-2

41. Voelker R. FDA approves bacteriophage trial. JAMA. 2019;321(7):638. https://doi.org/10.1001/jama.2019.0510