Bacteriophage therapy in the era of antimicrobial resistance: clinical evidence, translational challenges, and emerging regulatory frameworks (2020–2026)

Abstract

Antimicrobial resistance has intensified the search for alternatives to conventional antibiotics, particularly against multidrug-resistant bacterial pathogens that increasingly compromise treatment outcomes in hospitals and community settings. This narrative review examines bacteriophage therapy as an alternative for combating multidrug-resistant bacteria. Recent literature is discussed thematically, with emphasis on original studies, clinical datasets, translational experiments, and regulatory documents. The current evidence base consists predominantly of compassionate-use reports, small cohorts, and early-phase trials, including CRISPR-enhanced and inhaled phage platforms, which report safety observations, compartment-specific responses, and microbiome effects in individual studies. Mechanistic considerations discussed in the review include route-specific delivery, phage–host ecological interactions, resistance trade-offs, and phage–antibiotic synergy. While microbiological and clinical responses have been reported in individual studies, no confirmatory randomized trial has demonstrated clinical efficacy for any phage therapy indication. Manufacturing, standardization, and regulatory pathways for scaled deployment also remain unresolved. Regulatory developments in Europe, the United Kingdom, the United States, and Australia remain heterogeneous and predominantly access-based or compassionate-use-based rather than approval-based. Specific technical challenges include incomplete standardization of susceptibility testing and the need for robust monitoring of immune neutralization, endotoxin burden, and long-term ecological effects. Routine clinical adoption of phage therapy will ultimately depend on outcomes of adequately powered confirmatory trials, alongside resolution of manufacturing, regulatory, and standardization challenges.

Keywords

bacteriophage therapy / phage therapy / multidrug-resistant bacteria / antimicrobial resistance / ESKAPE pathogens / CRISPR-engineered phages

References

[1] World Health Organization. Global antibiotic resistance surveillance report 2025 [Internet]. World Health Organization; c2025 [cited 2026 May 27]. Available from: https://www.who.int/publications/i/item/9789240116337

[2] Medicines and Healthcare products Regulatory Agency (MHRA). Regulatory considerations for therapeutic use of bacteriophages in the UK [Internet]. MHRA; c2025 [2026 May 27]. Available from: https://assets.publishing.service.gov.uk/media/6908ce9c5e080b12248981a2/regulatory_considerations_for_therapeutic_use_of_bacteriophages_in_the_UK.pdf

[3] World Health Organization. WHO bacterial priority pathogens list, 2024: Bacterial pathogens of public health importance to guide research, development and strategies to prevent and control antimicrobial resistance [Internet]. Geneva: World Health Organization; c2024 [cited 2026 May 27]. Available from: https://www.who.int/publications/i/item/9789240093461?utm_

[4] Okesanya OJ, Ahmed MM, Ogaya JB, Amisu BO, Ukoaka BM, Adigun OA, et al. Reinvigorating AMR resilience: leveraging CRISPR-Cas technology potentials to combat the 2024 WHO bacterial priority pathogens for enhanced global health security-a systematic review. Trop Med Health. 2025; 53: 43.

[5] Moon K, Coxon C, Årdal C, Botgros R, Djebara S, Durno L, et al. Considerations and perspectives on phage therapy from the transatlantic taskforce on antimicrobial resistance. Nat Commun. 2025; 16: 10883.

[6] Nang SC, Lin YW, Petrovic Fabijan A, Chang RYK, Rao GG, Iredell J, et al. Pharmacokinetics/pharmacodynamics of phage therapy: a major hurdle to clinical translation. Clin Microbiol Infect. 2023; 29: 702-9.

[7] Petersen AØ, Damholt B, Grove M, Hink J, Marotte-Hurbon T, Söderqvist J, et al. Safety, recovery, and pharmacodynamics of CRISPR-Cas therapeutic SNIPR001: a phase 1, randomised, double-blind, first-in-human, dose-escalation study. Lancet Microbe. 2026; 7: 101257.

[8] Gorodnichev R, Shitikov E, Gurkova M, Kochetova T, Petrova M, Kuzovlev A, et al. Hospital-adapted inhaled phage therapy for ventilator-associated pneumonia caused by multidrug-resistant Klebsiella pneumoniae: a comparative pilot study. Crit Care. 2026; 30: 64.

[9] European Directorate for the Quality of Medicines & HealthCare (EDQM) / Council of Europe. Phage therapy medicinal products (5.31) [General chapter / Pharmacopoeial standard] [Internet]. 11th ed. European Pharmacopoeia Commission / EDQM; c2024 [cited 2026 May 27]. Available from: https://www.edqm.eu/documents/52006/277566/European%20Pharmacopoeia%20-%20Phage%20therapy%20medicinal%20products%20%285.31%29.pdf/d9da2e01-e002-32c9-b2eb-8a9360439c05?t=1727862827906

[10] Pirnay JP, Djebara S, Steurs G, Griselain J, Cochez C, De Soir S, et al. Personalized bacteriophage therapy outcomes for 100 consecutive cases: a multicentre, multinational, retrospective observational study. Nat Microbiol. 2024; 9: 1434-53.

[11] European Medicines Agency (EMA). Guideline on quality aspects of phage therapy medicinal products [Draft guideline] [Internet]. EMA (Committee for Medicinal Products for Human Use, CHMP / Biologics Working Party); c2025 [cited 2026 May 27]. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-quality-aspects-phage-therapy-medicinal-products_en.pdf

[12] Expanded Access [Internet]. U.S. Food and Drug Administration (FDA); [cited 2026 May 27]. Available from: https://www.fda.gov/news-events/public-health-focus/expanded-access

[13] Żaczek M, Weber-Dąbrowska B, Międzybrodzki R, Łusiak-Szelachowska M, Górski A. Phage Therapy in Poland - a Centennial Journey to the First Ethically Approved Treatment Facility in Europe. Front Microbiol. 2020; 11: 1056.

[14] Pires DP, Costa AR, Pinto G, Meneses L, Azeredo J. Current challenges and future opportunities of phage therapy. FEMS Microbiol Rev. 2020; 44: 684-700.

[15] Pirnay JP, Verbeken G, Ceyssens PJ, Huys I, De Vos D, Ameloot C, et al. The Magistral Phage. Viruses. 2018; 10: 64.

[16] Verbeken G, Pirnay JP. European regulatory aspects of phage therapy: magistral phage preparations. Curr Opin Virol. 2022; 52: 24-9.

[17] Djebara S, Lavigne R, Pirnay JP. Implementation challenges of personalised phage therapy. Lancet. 2025; 405: 1901-3.

[18] Zhang S, Ahn J. Phage Therapy as a Novel Alternative to Antibiotics Through Adaptive Evolution and Fitness Trade-Offs. Antibiotics. 2025; 14: 1040.

[19] Fukaya-Shiba A, Ogata A, Kuribayashi R, Sakurai A, Suzuki K, Takadama S, et al. Regulatory considerations for developing phage therapy medicinal products for the treatment of antimicrobial resistant bacterial infections. Front Pharmacol. 2025; 16: 1713471.

[20] Schooley RT. Translational research priorities for bacteriophage therapeutics. Essays Biochem. 2024; 68: 621-31.

[21] Niazi SK. Bacteriophage Therapy: Discovery, Development, and FDA Approval Pathways. Pharmaceuticals. 2025; 18: 1115.

[22] Fuerst-Wilmes M, Respondek V, Schramm M, Lilienthal N, Buss K, Duechting A. Regulation of phage therapy medicinal products: developments, challenges, and opportunities. Front Cell Infect Microbiol. 2025; 15: 1631359.

[23] Roque-Borda CA, Zhang Q, Nguyen TPT, Nguyen TTH, Medhi H, Rodrigues HLS, et al. Synergistic combinations of antimicrobial peptides and conventional antibiotics: A strategy to delay resistance emergence in World Health Organization priority bacteria. Pharmacol Rev. 2026; 78: 100104.

[24] Lucero-Prisno DE, Okesanya OJ, Agboola AO, Adebayo UO, Adigun OA, Ahmed MM, et al. Emerging technologies and innovative approaches to combat antimicrobial resistance: A narrative review of next-generation therapeutic strategies. Next Bioeng. 2025; 1: 100003.

[25] GBD 2021 Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance 1990-2021: a systematic analysis with forecasts to 2050. Lancet. 2024; 404: 1199-226.

[26] Bumunang EW, Zaheer R, Niu D, Narvaez-Bravo C, Alexander T, McAllister TA, et al. Bacteriophages for the Targeted Control of Foodborne Pathogens. Foods. 2023; 12: 2734.

[27] Baud A, Rougis I, Bertolla F. A Century-Old Solution for 21st Century Challenges: Current Applications with a Focus on Biocontrol, Environmental Impacts, and Regulatory Perspectives. Antibiotics. 2026; 15: 180.

[28] Ngene AC, Umar U. Bacteriophage applications and future prospects for addressing challenges in African agrifood systems. Discov Food. 2025; 5: e5.

[29] Rivera-Lopez EO, Tirko NN, Dudley EG. Regulatory Landscape and the Potential of Bacteriophage Applications in the United States’ Food Industry. J Food Prot. 2025; 88: 100510.

[30] Sahoo K, Meshram S. The Evolution of Phage Therapy: A Comprehensive Review of Current Applications and Future Innovations. Cureus. 2024; 16: e70414.

[31] Olszewska P, Spietelun M, Syguła K, Ossowski A, Grygorcewicz B. Bacteriophages as a modern diagnostic tool: innovations, applications and challenges. Mol Biol Rep. 2025; 52: 997.

[32] Karamlou S, Aghajani E, Familsamavati M, Azad NF, Arayesh S, Mohsenipour Z. Bacterial resistance to phage therapy: Mechanisms and strategies to overcome it. Curr Mol Pharmacol. 2025; 18: 108-22.

[33] Cui L, Watanabe S, Miyanaga K, Kiga K, Sasahara T, Aiba Y, et al. A Comprehensive Review on Phage Therapy and Phage-Based Drug Development. Antibiotics. 2024; 13: 870.

[34] Ranveer SA, Dasriya V, Ahmad MF, Dhillon HS, Samtiya M, Shama E, et al. Positive and negative aspects of bacteriophages and their immense role in the food chain. npj Sci Food. 2024; 8: 1.

[35] Strathdee SA, Hatfull GF, Mutalik VK, Schooley RT. Phage therapy: From biological mechanisms to future directions. Cell. 2023; 186: 17-31.

[36] Palma M, Qi B. Advancing Phage Therapy: A Comprehensive Review of the Safety, Efficacy, and Future Prospects for the Targeted Treatment of Bacterial Infections. Infect Dis Rep. 2024; 16: 1127-81.

[37] Hitchcock NM, Devequi Gomes Nunes D, Shiach J, Valeria Saraiva Hodel K, Dantas Viana Barbosa J, Alencar Pereira Rodrigues L, et al. Current Clinical Landscape and Global Potential of Bacteriophage Therapy. Viruses. 2023; 15: 1020.

[38] Chen J, Duan C, Zhang K, Liu J, Han C. Phage Therapy: Targeting the Gut Microbiota for the Treatment of Acute Pancreatitis. J Gastroenterol Hepatol. 2026; 41: 1446-58.

[39] Kim P, Sanchez AM, Penke TJR, Tuson HH, Kime JC, McKee RW, et al. Safety, pharmacokinetics, and pharmacodynamics of LBP-EC01, a CRISPR-Cas3-enhanced bacteriophage cocktail, in uncomplicated urinary tract infections due to Escherichia coli (ELIMINATE): the randomised, open-label, first part of a two-part phase 2 trial. Lancet Infect Dis. 2024; 24: 1319-32.

[40] Selim HMRM, Gomaa FAM, Alshahrani MY, Morgan RN, Aboshanab KM. Phage therapeutic delivery methods and clinical trials for combating clinically relevant pathogens. Ther Deliv. 2024; 16: 247-69.

[41] Chan BK, Stanley GL, Kortright KE, Vill AC, Modak M, Ott IM, et al. Personalized inhaled bacteriophage therapy for treatment of multidrug-resistant Pseudomonas aeruginosa in cystic fibrosis. Nat Med. 2025; 31: 1494-501.

[42] Vaezi A, Healy T, Ebrahimi G, Rezvankhah S, Hashemi Shahraki A, Mirsaeidi M. Phage therapy: breathing new tactics into lower respiratory tract infection treatments. Eur Respir Rev. 2024; 33: 240029.

[43] Beloborodova NV, Grechko AV, Gurkova MM, Zurabov AY, Zurabov FM, Kuzovlev AN, et al. Adaptive Phage Therapy in the Treatment of Patients with Recurrent Pneumonia (Pilot Study). Gen Reanimatol. 2021; 17: 4-14.

[44] Weissfuss C, Li J, Behrendt U, Hoffmann K, Bürkle M, Tan C, et al. Adjunctive phage therapy improves antibiotic treatment of ventilator-associated-pneumonia with Pseudomonas aeruginosa. Nat Commun. 2025; 16: 4500.

[45] Ross FC, Patangia D, Grimaud G, Lavelle A, Dempsey EM, Ross RP, et al. The interplay between diet and the gut microbiome: implications for health and disease. Nat Rev Microbiol. 2024; 22: 671-86.

[46] Siopi M, Skliros D, Paranos P, Koumasi N, Flemetakis E, Pournaras S, et al. Pharmacokinetics and pharmacodynamics of bacteriophage therapy: a review with a focus on multidrug-resistant Gram-negative bacterial infections. Clin Microbiol Rev. 2024; 37: e0004424.

[47] Gencay YE, Jasinskytė D, Robert C, Semsey S, Martínez V, Petersen AØ, et al. Engineered phage with antibacterial CRISPR-Cas selectively reduce E. coli burden in mice. Nat Biotechnol. 2023; 42: 265-74.

[48] Furfaro LL, Payne MS, Chang BJ. Bacteriophage Therapy: Clinical Trials and Regulatory Hurdles. Front Cell Infect Microbiol. 2018; 8: 376.

[49] Gallina A, Gallina M, Cona A, Vitulo P, Mularoni A, Provenzani A. Phage Therapy at the Crossroads Between Clinical Promise and Regulatory Challenge. Pharmaceuticals. 2026; 19: 162.

[50] Torriero-Smith N, Rogers BA, McDonald MJ, Barr JJ. Harnessing ‘phage training’ to bolster the therapeutic potential of bacteriophages. Curr Opin Microbiol. 2026; 89: 102696.

[51] Zhou Z, Fu H, Li M, Han Z, Wu Z, Fan H, et al. Bacteriophage Therapy: Current Strategies and Future Perspectives. MedComm. 2026; 7: e70645.

[52] Jdeed G, Kravchuk B, Tikunova NV. Factors Affecting Phage-Bacteria Coevolution Dynamics. Viruses. 2025; 17: 235.

[53] Oromí-Bosch A, Antani JD, Turner PE. Developing Phage Therapy That Overcomes the Evolution of Bacterial Resistance. Annu Rev Virol. 2023; 10: 503-24.

[54] Brives C, Froissart R, Perez-Sepulveda B, Le Marrec C. Thinking Phage Innovations Through Evolution and Ecology. PHAGE: Ther Appl Res. 2024; 5: 5-13.

[55] Williams J, Severin J, Temperton B, Mitchelmore PJ. Phage Therapy Administration Route, Regimen, and Need for Supplementary Antibiotics in Patients with Chronic Suppurative Lung Disease. PHAGE. 2023; 4: 4-10.

[56] Petrovic Fabijan A, Lin RCY, Ho J, Maddocks S, Ben Zakour NL, Iredell JR, et al. Safety of bacteriophage therapy in severe Staphylococcus aureus infection. Nat Microbiol. 2020; 5: 465-72.

[57] Supina BSI, Dennis JJ. The Current Landscape of Phage-Antibiotic Synergistic (PAS) Interactions. Antibiotics. 2025; 14: 545.

[58] Masterson K, Major I, Lynch M, Rowan N. Synergy Assessment of Four Antimicrobial Bioactive Compounds for the Combinational Treatment of Bacterial Pathogens. Biomedicines. 2023; 11: 2216.

[59] Cresswell K, Claire R, Issa L, Kubehl L, Bilal O, Purcell R, et al. Best Practices and Gaps in Current Regulatory and Health Technology Assessment Real-World Evidence Policies for Medicines and Medical Devices: Current State of Play and Next Steps. Clin Transl Sci. 2026; 19: e70507.

[60] Marino A, Stracquadanio S, Cosentino F, Maraolo AE, Colpani A, De Vito A, et al. Phage to ESKAPE: Personalizing Therapy for MDR Infections-A Comprehensive Clinical Review. Pathogens. 2025; 14: 1011.

[61] Paul K, Merabishvili M, Hazan R, Christner M, Herden U, Gelman D, et al. Bacteriophage Rescue Therapy of a Vancomycin-Resistant Enterococcus faecium Infection in a One-Year-Old Child following a Third Liver Transplantation. Viruses. 2021; 13: 1785.

[62] Rodriguez JM, Woodworth BA, Horne B, Fackler J, Brownstein MJ. Case Report: successful use of phage therapy in refractory MRSA chronic rhinosinusitis. Int J Infect Dis. 2022; 121: 14-6.

[63] Tan X, Chen H, Zhang M, Zhao Y, Jiang Y, Liu X, et al. Clinical Experience of Personalized Phage Therapy Against Carbapenem-Resistant Acinetobacter baumannii Lung Infection in a Patient With Chronic Obstructive Pulmonary Disease. Front Cell Infect Microbiol. 2021; 11: 631585.

[64] Sippel K, Velimirov B. Phage Therapy: Application and Related Problems-A Review. Life. 2025; 16: 57.

[65] Special Access Scheme (SAS): Guidance for health practitioners accessing unapproved therapeutic goods [Internet]. Therapeutic Goods Administration (TGA); c2024 [cited 2026 May 28]. Available from: https://www.tga.gov.au/resources/guidance/special-access-scheme-sas-guidance-health-practitioners-accessing-unapproved-therapeutic-goods

[66] Proposed GMP exemption for certain bacteriophage manufacture [Internet]. Therapeutic Goods Administration; c2026 [cited 2026 May 28]. Available from: https://consultations.tga.gov.au/medicines-regulation-division/proposed-gmp-exemption-for-phage-manufacture/

[67] Coxon C, Bell E, Adriaenssens E, Clark J, Edwards J, Gohir T, et al. Interpretation guidance for MHRA regulatory considerations for phage therapeutic products. Microbiology. 2025; 171: e171.

[68] Yang Q, Le S, Zhu T, Wu N. Regulations of phage therapy across the world. Front Microbiol. 2023; 14: 1250848.

[69] Alvarez RD, Årdal C, Classen AY, Nagel TE, Ceyssens PJ, German GJ. Cross-border dialogue: An international survey of regulators on phage therapy. Int J Antimicrob Agents. 2025; 66: 107614.

[70] Zalewska-Piątek B. Phage Therapy-Challenges, Opportunities and Future Prospects. Pharmaceuticals. 2023; 16: 1638.

[71] Malik S, Ahsan O, Muhammad K, Munawar N, Waheed Y. Phagetherapy updates: New frontiers against antibiotic resistance. Eur J Microbiol Immunol. 2025; 15: 1-12.

[72] Verbeken G, Huys I, Pirnay JP, Jennes S, Chanishvili N, Scheres J, et al. Taking Bacteriophage Therapy Seriously: A Moral Argument. BioMed Res Int. 2014; 2014: 621316.

[73] Pacia DM, Brown BL, Minssen T, Darrow JJ. CRISPR-phage antibacterials to address the antibiotic resistance crisis: scientific, economic, and regulatory considerations. J Law Biosci. 2024; 11: lsad030.

[74] Oliveira M, Antunes W, Mota S, Madureira-Carvalho Á, Dinis-Oliveira RJ, Dias da Silva D. An Overview of the Recent Advances in Antimicrobial Resistance. Microorganisms. 2024; 12: 1920.

[75] Pinheiro F. Predicting the evolution of antibiotic resistance. Curr Opin Microbiol. 2024; 82: 102542.