Abstract
Bacteriophages (phages) — viruses that selectively infect bacteria — are a promising option for personalized therapy of difficult-to-treat bacterial infections. Clinical implementation in many countries worldwide, however, faces multiple hurdles, including a lack of consensus on general principles for phage therapy, infrastructural requirements, procedures for quality-assured phage selection and preparation, clinical administration, monitoring and documentation. Existing guidance provides limited practical direction across the entire translational pathway and lacks inspection-ready specifications to support both pharmacies and clinical sites. These gaps impede safe and transparent clinical use and effective regulatory oversight. Likewise, there are no established processes to identify research questions that will be key to advancing clinical phage research in the future. To address these needs, this consensus-based guideline was developed within the methodological framework of the Association of the Scientific Medical Societies in Germany under the leadership of the German Society for Infectious Diseases. It was created through a collaborative effort involving 20 professional societies, patient advocacy groups and regulatory authorities and 18 international experts. The guideline provides over 60 recommendations on core principles, infrastructure, preparation and quality control, administration and future research. Recommendations are supported by international societies, organizations and stakeholders. By providing clear and practice-oriented recommendations, this consensus statement paves the way for the safe and standardized use of personalized phage therapy.
Main
The accelerating global crisis of antimicrobial resistance poses an existential threat to modern medicine, driving renewed interest in bacteriophage (phage) therapy as a targeted approach for the treatment of bacterial infections. Despite growing clinical use, often as a last-resort intervention, broader implementation of personalized phage therapy in many regions of the world remains constrained by the absence of clear, harmonized and practice-oriented guidance. This gap is becoming increasingly evident as physicians, pharmacists, patients and regulators seek structured pathways for integrating personalized phage therapy into clinical care when conventional antimicrobial options have failed.
This guideline aims to address this unmet need by providing practical, consensus-based recommendations for safe and effective personalized phage therapy in Germany and beyond. It focuses on core principles underpinning phage therapy, infrastructural and organizational requirements, standards for phage preparation and quality control, clinical administration considerations and priorities for future translational and clinical research. This document seeks to translate foundational principles into actionable guidance applicable to real-world clinical settings.
The guideline was developed by an international and interdisciplinary group of experts. This collaboration integrated clinical expertise in infectious diseases, clinical microbiology and various medical specialties with technical knowledge in pharmacology, toxicology and biotechnology as well as regulatory and quality affairs. National and international phage experts, as well as representatives from patient advocacy groups, were actively involved from an early stage to ensure inclusivity, relevance and alignment with clinical and societal needs. The final recommendations have been reviewed and supported by additional key international societies, organizations and stakeholders, underscoring their broad acceptance and applicability.
All recommendations were formulated using a structured, consensus-based methodology in accordance with the standards of the Association of the Scientific Medical Societies in Germany (AWMF) for consensus-based guidelines. Structured consensus techniques were applied under neutral moderation by AWMF representatives to ensure transparency, rigor and balance.
Given the biological, clinical and regulatory complexity of phage therapy, as well as the limited available evidence, this guideline does not aim to be exhaustive or to address every possible clinical scenario. Rather, it provides a structured framework to support clinicians, pharmacists, researchers and policymakers in navigating the key challenges of personalized phage therapy and advancing its responsible integration into contemporary medical practice.
Methodology
This consensus guideline was developed within the structured methodological framework of the AWMF under the leadership of the German Society for Infectious Diseases (Deutsche Gesellschaft für Infektiologie e.V. (DGI)). The panel comprised representatives from 20 German medical societies, German patient representatives and experts from national and international institutions and authorities, including German regulatory agencies and academic centers (Supplementary Methods, Tables 1 and 2).
A steering committee (Supplementary Methods, Table 3) supervised the process, supported by neutral methodological guidance from AWMF representatives. Six topic-specific working groups were convened (Supplementary Methods, Table 4). After an initial online meeting defining key questions and literature search strategies, each working group conducted independent literature reviews and drafted recommendations with supporting background texts.
Recommendations were discussed and voted on during six online consensus conferences neutrally moderated by an AWMF representative. Voting included plenary discussion, amendments where necessary and formal voting. The strength of recommendations was determined by standardized wording and grading (Supplementary Methods, Table 5): strong recommendations were expressed using the wording ‘we recommend/we do not recommend’ or ‘should/should not’ (grade A); conditional recommendations were expressed using ‘we suggest’, ‘ought to’ or ‘can/cannot’ (grade B); and open recommendations were expressed using ‘may be considered’, ‘could be considered’ or ‘might be considered’ (graded as ‘Optional’). The strength of consensus was classified according to predefined categories (Supplementary Methods, Table 6) based on the proportion of approving participants: strong consensus (>95%), consensus (>75–95%), majority approval (>50–75%) and no consensus (≤50%). Expository content describing specific facts, circumstances or problems without direct recommendations for action was designated as ‘statements’; these did not require formal voting and were not assigned a formal level of evidence. The guideline is valid from 5 January 2026 to 29 June 2030. The revision will be initiated by the steering committee that will also review the need for updates to the guideline annually. Full methodological details are provided in the Supplementary Methods.
All participants submitted conflict of interest (COI) declarations via the AWMF online portal (Supplementary File 1). Moderate COIs were identified for seven individuals, who were excluded from leadership roles. To assess any potential influence, the consensus analysis was repeated both including and excluding their votes. As the results were unchanged, their voting did not affect the final consensus outcomes. The guideline was externally reviewed, adopted by participating societies and circulated for review and support by international societies, organizations and stakeholders (Supplementary Methods, Tables 7 and 8).
A list of important abbreviations commonly used throughout this paper is provided in the Supplementary Explanations.
This guideline is directed at physicians involved in the treatment of bacterial infections in adult and pediatric patients, particularly those working in infectious disease management, antimicrobial stewardship and related medical and pharmaceutical fields. It further serves a broader audience, including clinicians outside the core specialties, pharmacists, patients and patient advocacy organizations, ethics committees, researchers in microbiology, infectious diseases and personalized medicine, regulatory bodies and public health authorities, policymakers, hospital administrators, health insurance providers and industry stakeholders in phage research and development.
General considerations and regulatory frameworks for phage therapy
Originally pioneered by Twort and d’Hérelle to combat enteric and wound infections, phage therapy fell out of favor during the antibiotic era. Today, however, the global crisis of antimicrobial resistance has sparked a renewed interest in these viral treatments1,2,3,4,5,6. Phages are abundant in nature and the human microbiome7,8,9,10,11,12,13, vary widely in structure and genome size and follow different life cycles, with lytic phages forming the basis of phage therapeutics14,15. Moreover, the potential for bacterial resistance to phages requires continued monitoring and iterative adjustment during treatment. Available evidence suggests that phage therapy is generally safe when produced and administered according to quality standards, and first considerations for the use of phage therapy in clinical practice have been suggested to inform clinicians16,17,18,19,20. In one series of 100 consecutive cases treated in Belgium, 77% of patients showed clinical improvement and 61% achieved bacterial eradication, with no serious phage-related adverse reactions21. Alongside the Belgian 100-patient case series, several systematic reviews have further characterized this field. A recent systematic review of safety and efficacy trials found that, although phage therapy is consistently reported to be safe in modern trials, efficacy has not been reliably demonstrated22. The authors attribute this discrepancy to key limitations in trial design, particularly the failure to deliver sufficient quantities of appropriately matched phages to the site of infection. Similarly, a systematic review focusing specifically on difficult-to-treat infections concluded that phage therapy shows a favorable safety profile and potential clinical benefit, particularly in compassionate-use settings, while emphasizing the heterogeneity of treatment approaches and the limited availability of controlled clinical data20. Collectively, these findings support the overall safety of phage therapy and its therapeutic promise while underscoring the need for optimized treatment strategies and well-designed prospective trials to better establish efficacy.
Assessing phage activity relies on plaque, spot and liquid infection assays to generate phagograms, although reproducibility across laboratories remains limited.
The standard authorization pathway for medicinal products, based on randomized controlled clinical trials using investigational medicinal products manufactured according to Good Manufacturing Practice (GMP), presents major challenges for personalized phage therapy23 (Fig. 1). Phage specificity requires individualized matching, which, alongside dynamic bacteria–phage interactions and the need for treatment adaptation, limits the standardization and scalability of such trials. Although early-phase studies suggest a favorable safety profile, the highly individualized nature of these treatments remains fundamentally incompatible with current regulatory frameworks24,25,26,27,28,29,30.
Even outside the highly regulated environment of clinical trials, individualized phage administrations are often constrained by regulatory and practical barriers. GMP-grade phage manufacture is costly, time-consuming and often incompatible with the urgency and flexibility required for and during personalized therapy, making it feasible for only a small subset of patients when suitable GMP-grade phages are already available. Consequently, many personalized treatments have relied on non-GMP-grade phages, as documented in case reports worldwide20,21,31,32,33,34,35,36,37,38,39.
Magistral preparation of phage active pharmaceutical ingredients (APIs) — the purified phage preparations used as starting materials — and phage therapy medicinal products (PTMPs), which are the finished formulations intended for patient administration, offers a pragmatic alternative, as such preparations are generally exempt from GMP requirements. For example, in the European Union, under Article 3(1) of Directive 2001/83/EC, personalized phage preparations compounded as magistral formulations on prescription fall under this exemption. Nevertheless, existing professional guidance provides insufficient detail to ensure the consistent preparation of phage APIs or PTMPs. Although the European Pharmacopoeia (Ph.Eur) has recently issued baseline guidance for phage therapy16, the lack of detailed, practice-oriented standards continues to limit broader implementation. In most countries worldwide, the cross-border transfer of magistral phage preparations to individual patients remains challenging. Inconsistencies in quality standards, restricted and inflexible manufacturing capacity, limitations in traceability and stability, including cold-chain requirements, liability and insurance issues related to transfers and logistical constraints at customs can all restrict flexibility and lead to substantial delays.
Given the growing number of patient requests and the limitations of existing regulatory pathways, this guideline emphasizes immediately applicable, patient-individualized approaches that complement industrial phage development rather than awaiting future legislative changes that may not address urgent clinical needs.
Recommendations on general principles of personalized bacteriophage therapy
Phage therapy should be considered on a case-by-case basis, mainly for patients in whom standard-of-care treatments have failed or are contraindicated. Outside clinical trials, phage therapy is typically applied within the framework of individualized treatment attempts, particularly for difficult-to-treat infections, which can be caused, for example, by antibiotic-resistant or biofilm-forming bacteria21,40,41,42,43,44. Because phage therapy is highly specific (see also Supplementary Explanations, Fig. 1), successful treatment requires culture-based bacterial identification with species determination, followed by careful phage–bacteria matching. The susceptibility of the bacteria to the chosen phage(s) should be confirmed as close to treatment initiation as possible, as susceptibility to phages may change over time. In urgent situations, therapy may begin before susceptibility results are available and be adapted thereafter. In case of polymicrobial infections, all causative bacterial species should undergo phage susceptibility testing, as untreated bacteria may sustain an infection despite targeted therapy of a single organism, and comprehensive testing improves the likelihood of clinical success. Interdisciplinary discussions among treating physicians, microbiologists, infectious disease specialists and experts involved in phage selection, manufacturing, susceptibility testing and treatment are essential.
When quality standards are met, phage therapy appears safe16,17,18,20. Despite limited evidence from clinical trials, the available data indicate no major safety concerns, including immunocompromised patients, children and pregnant or breastfeeding women18,20,21,28,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74. Beyond biologically expected responses (for example, fever and increased byproducts due to bacterial breakdown), no clinically relevant drug interactions or allergic reactions attributable to phage therapy have been reported, although monitoring remains advisable18,19,57,75,76.
The guideline team proposes the following recommendations and statements on general principles of personalized phage therapy (Table 1). The full set of background explanations is provided in Supplementary Explanations 1.
Recommendations on infrastructure of personalized bacteriophage therapy
Safe, efficient and scalable implementation of personalized phage therapy requires a coordinated infrastructure that integrates laboratory diagnostics, phage preparation and clinical expertise. Core elements include access to phage laboratories capable of performing phage screening and susceptibility testing, appropriate facilities for phage preparation with defined quality control and safety standards and an interdisciplinary phage therapy board that brings together relevant medical specialists, infectious diseases experts, microbiologists and pharmacists to guide clinical case assessment and individual treatment strategies (Supplementary Explanations, Fig. 2). These components form an ideal, flexible framework and do not need to be housed at a single site; certain elements, such as phage preparation, may be outsourced to specialized centers.
Phage therapy is not limited to highly specialized centers, but any institution administering phages must meet minimum requirements, including appropriate storage conditions, medically qualified personnel and the ability to manage phage administration, safety monitoring, concomitant therapies and microbiological sampling. Institutions without in-house capacities for phage assays, such as susceptibility or phage–antibiotic synergy testing, may rely on external laboratories, provided results are available in a timely manner. Standardized and harmonized methods for phage susceptibility and potency testing are essential, with an emphasis on interlaboratory proficiency testing. Referential guidance may be provided through recommendations currently under development by the subcommittee on phage susceptibility testing of the European Committee on Antimicrobial Susceptibility Testing (EUCAST)77.
Comprehensive documentation of phage therapy cases in national and/or international registries, including treatment protocols, outcomes and unexpected events, is considered essential to improve transparency, enable systematic evaluation and inform future practice78. High-quality and harmonized data collection is viewed as critical for the long-term success of personalized phage therapy.
The recommendations and statements on infrastructure of personalized phage therapy are summarized in Table 2. A comprehensive list of all explanatory text is available in Supplementary Explanations 2.
Recommendations on preparation, quality control, labeling and storage of personalized phage therapeutics
Phage preparation for therapeutic use (Fig. 2) begins with the identification of suitable phages active against the bacterial target, which may be sourced from established phage collections or seed lots, environmental or human samples or synthetic and/or genetically engineered phages. Genetically engineered phages may also be used to improve therapeutic suitability, for example by removing lysogeny-associated genes to ensure a lytic lifecycle. Notably, engineered phages have entered clinical evaluation, including CRISPR–Cas-enhanced bacteriophage cocktails targeting Escherichia coli in urinary tract infections (for example, LBP-EC01, phase 1b/2 clinical trials, NCT05488340) as well as in case reports covering other indications61,79. However, such modifications may introduce risks, including recombination events, and entail additional regulatory and biosafety considerations, although this is not currently considered a major risk. It is advisable that their use be supported by thoughtful risk assessment and appropriate regulatory oversight.
Phage adaptation may be employed to enhance antimicrobial efficacy by evolving one or more phages on a patient’s clinical isolate to broaden host range or increase activity.
Phage APIs must be prepared from well-characterized phage and bacterial seed lot systems (Fig. 2 and Supplementary Explanations, Fig. 3) to ensure clonal origin, genetic stability and appropriate quality, including identity, potency, appearance, sterility and purity16,80,81,82,83,84,85,86. For more information on the determination of these attributes, see Supplementary Explanations, Tables 1 and 2, and Supplementary Explanations, Figs. 3 and 4.
Phage preparation typically involves propagation of phages in defined bacterial hosts, followed by purification to remove bacterial impurities while preserving phage activity16,17,83. Supplementary Explanations, Fig. 5 shows an overview of an upstream and downstream process, comprising bacterial cultivation and phage propagation followed by purification.
Phage propagation requires a susceptible bacterial host. Ideally, these strains are selected from established master cell banks to ensure that they are free of resistance gene and mobile genetic elements or genetic elements supporting the synthesis of toxins or virulence factors16. Whole-genome sequencing can be used to verify the absence of these elements and any inducible prophage or phage-like sequences. In situations where no host strain matching the required phage from an established master cell bank is readily available, the patient’s own clinical isolate may be used for PTMP preparation. In this case, undesirable genetic features do not necessarily disqualify the strain; because these elements originated within the patient, using the isolate as a production host introduces no incremental safety risk, provided a formal risk assessment is conducted (for more details, see also Supplementary Explanations, Table 2).
Cultivation conditions, including temperature, medium, duration, shaking and multiplicity of infection, must be optimized for each specific phage−host combination.
Phage APIs are formulated into PTMPs according to the intended indication and route of administration, potentially with excipients selected to enable effective delivery and enhance product stability. Formulations may be liquid, solid, semi-solid or device associated (for example, phage-coated wound dressing), supporting diverse administration routes. Stability and storage conditions should be validated to maintain safety and efficacy36,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104. PTMPs may be administered via multiple routes, including topical, intravenous, inhalational, oral, intravesical, intra-articular, intrathecal and others, and different routes may be combined as clinically indicated. Each API and PTMP must be accompanied by a preparation label ensuring unambiguous identification as well as a supplementary information sheet providing detailed preparation-related information supplied separately from the packaging105.
Although magistral preparations are exempt from industrial GMP, they must meet current scientific standards and be produced in controlled environments by qualified personnel83. Quality control of phage APIs and PTMPs may be performed by qualified laboratories with appropriate phage expertise and in adherence to this guideline, using retained samples not intended for patient administration. Quality control steps include, as appropriate, identity, potency, purity and microbiological quality, pyrogenicity, genomic purity, protein contamination, prophages/temperate phages, pH, appearance, hemolytic activity and residual agents, with risk-adapted flexibility for urgent therapies. Supplementary Explanations, Table 2 details consented quality and safety requirements for (1) preparation environments such as air quality, (2) equipment, materials and preparation processes such as culture media, (3) phage seed lots such as identification, (4) phage APIs such as purification, (5) PTMPs such as stability in combined preparations and (6) bacterial working cell banks such as prophages.
Regarding the quality aspect of microbiological quality/sterility, non-sterile APIs or PTMPs must meet the microbiological thresholds defined in Ph.Eur. 5.1.4 and are intended for non-sterile administration routes such as oral, cutaneous or nasal use. Non-sterile APIs/PTMPs with high microbiological quality (Ph.Eur. 2.6.12 and 2.6.27) must achieve 0 colony-forming units (CFU) per milliliter or per gram and may be used for intravenous administration in emergencies, wound applications or short shelf-life products. Sterile APIs/PTMPs must comply with sterility requirements (Ph.Eur. 2.6.1 and 5.1.6) and are intended for intravenous use in non-emergency cases or for off-the-shelf preparations.
Endotoxin levels represent a critical quality attribute in the development of personalized phage therapeutics, as they directly influence purification strategies, formulation and the feasible dose for clinical application. Phage preparations require downstream purification (for example, anion exchange chromatography, endotoxin-binding resins, ultrafiltration and ultracentrifugation) to reduce endotoxins and host-derived impurities, with additional steps to remove process chemicals if needed. Endotoxin levels are quantified using standard assays (for example, recombinant Factor C, monocyte activation test) and must be reported to ensure compliance of the final product with regulatory limits, typically approximately 5 endotoxin units per kilogram of body weight per hour (EU kg−1 h−1) for parenteral use106,107, with possible route-dependent adjustments. For more details, see also Supplementary Explanations, Table 2.
Phage stability should be systematically evaluated using quantitative titering methods, such as the double agar overlay (DAO) method, as described in the forthcoming Ph.Eur. General Chapter 2.7.38. Factors influencing stability include temperature, pH, ultraviolet exposure, ionic strength, purity, adsorption to matrices, shear stress and phage concentration91,108,109. Testing under conditions reflecting intended use, including in biological fluids, can inform formulation, excipient selection and administration strategy. Storage conditions for each phage and formulation should be determined experimentally if not provided by the supplier (for more details, see Supplementary Explanations, Table 2, and Background R4-13−R4-15).
Consensus-based definitions related to the phage preparation process are provided in Supplementary Explanations, Table 1. The recommendations on preparation, quality control, labeling105, documentation83,110 and storage of personalized phage therapeutics are summarized in Table 3, and the complete set of explanatory text is provided in Supplementary Explanations 3.
Recommendations on administration of personalized phage therapy
Phage therapy has been applied to a wide range of bacterial infections, particularly those affecting skin and soft tissues, bones and joints, cardiac devices, bloodstream and respiratory tract as well as the urogenital and gastrointestinal systems18,21,111. Patient-centered planning of phage therapy should be individualized and take into account the patient’s history of preceding antibiotic or phage treatments; prior interventions or surgeries; extent, localization and severity of infection; presence of prosthetic or other foreign material; underlying conditions; allergies; co-medication including ongoing anti-infective therapy; and overall clinical status.
Phage therapy should also be personalized regarding phage composition (single phage, sequential therapy or cocktails; see also Supplementary Explanations, Fig. 6), dose, route, formulation, timing, frequency and duration, with adjustments made dynamically during therapy18,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126. Optimal phage titers depend on bacterial density, growth rate, site-specific conditions and administration route, acknowledging that excessive or insufficient titers may compromise efficacy. Phage stability during preparation and delivery, including potential losses from administration devices or gastric acidity, must be considered89,94,127,128,129,130. Detailed explanations on how to address these aspects, including the use of phage cocktails versus sequential therapy and phage titer, are provided in Supplementary Explanations 4.
After comprehensive patient counseling and informed consent, treatment is generally initiated in an inpatient setting, with monitoring of vital signs, laboratory markers, microbiological cultures including ongoing phage susceptibility testing during phage therapy and, where appropriate, analyses of phage distribution at the target site and immune responses.
Follow-up duration after phage therapy should be established through interdisciplinary decision-making involving phage experts, microbiologists and infectious disease specialists. Informed by prior experience, follow-up should ideally be at least several months, extended for chronic infections where feasible, and harmonized with other infection management strategies.
A summary of the recommendations on the administration of personalized phage therapy is presented in Table 4, with the complete background available in Supplementary Explanations 4. A representative draft of an informed consent form is included (Supplementary File 3).
Recommendations on future research priorities to improve implementation and efficacy of phage therapy
Despite growing interest in phage therapy as a potential alternative or adjunct to antibiotics, the current clinical evidence base remains limited. In particular, there is a notable lack of large, well-powered randomized controlled trials that comprehensively assess efficacy and optimize treatment regimens across indications. To date, only a small number of randomized controlled trials have been completed. For example, the PhagoBurn trial, which evaluated phage therapy for burn wound infections, highlighted both the feasibility and the challenges of conducting such studies, including issues related to phage stability, dosing and regulatory constraints26. Similarly, a randomized trial in chronic otitis caused by Pseudomonas aeruginosa reported some evidence of clinical benefit, although the trial was limited by its small sample size and narrow scope131. Other controlled trials, including those investigating urinary tract infections and acute diarrheal disease, have yielded mixed or inconclusive findings24,28. More recently, the Locus Biosciences trial targeting urinary tract infections provided additional evidence supporting the feasibility of phage-based approaches in this indication, although further validation is required132.
Notably, a growing number of clinical trials are currently ongoing or in preparation, reflecting increasing clinical interest in phage therapy. Collectively, existing and forthcoming trials underscore both the therapeutic potential of phage therapy and the substantial methodological and practical challenges that remain. Heterogeneity in study design, phage selection and manufacturing, dosing strategies and clinical endpoints further complicates direct comparisons across studies.
Given the impracticality of conducting trials for every phage−bacterium pairing, advancement of the field will require well-designed use cases, standardized outcome reporting (for example, through international registries such as Phagistry78) and n-of-1 trial designs. Artificial intelligence and mathematical modeling are expected to accelerate phage research by enabling host−range prediction, reducing laboratory screening and improving pharmacokinetic−pharmacodynamic optimization133.
Key research priorities (Supplementary Explanations, Fig. 7) include systematic studies correlating clinical outcomes with laboratory-based phage susceptibility testing to improve prediction of therapeutic efficacy134,135,136. In line, harmonization of susceptibility testing across liquid, solid and biofilm models, alongside the development of rapid diagnostic tools, is essential. Special attention is needed for biofilm-associated and polymicrobial infections, where predictive models remain weak.
Understanding phage−phage and phage−antibiotic interactions is another priority, as these combinations can be synergistic or antagonistic depending on context31,60,137,138. Standardized methods to evaluate such interactions, including in polymicrobial settings, are required.
Phage-resistant bacterial variants frequently emerge during or after therapy, contributing to persistent infections and treatment failure21. Mechanistic insights into resistance development, including non-genomic adaptations, are critical for designing effective interventions. In addition, the evolutionary costs associated with resistance, such as reduced motility or restored antibiotic susceptibility, offer potential therapeutic leverage118,121,122,124,125.
Phage behavior in patients can be affected by site-specific physiological conditions, including low pH, bile acids and ion concentrations139,140. The host immune system might further modulate phage pharmacokinetics, with mechanisms such as phage endocytosis and pre-existing or induced antibodies141,142,143, underscoring the need for systematic investigation to guide optimized administration strategies.
Effective clinical translation also depends on optimized phage formulation and delivery strategies to ensure stability, activity, persistence and reduced immunogenicity. Innovations in encapsulation and nanoparticles, along with systematic evaluation of dosing, timing and treatment duration, are central for safe, effective and scalable phage therapies91,92,93,94,95,97,144.
Targeted genetic modifications can expand the therapeutic scope of phages by altering receptor-binding proteins or removing lysogeny genes, thereby overcoming narrow host ranges or unlocking previously unusable temperate phages63.
Current purification approaches, including endotoxin removal, are often labor-intensive and costly and reduce phage titers. Innovations such as cell-free phage production145,146,147 and optimized purification protocols are needed to enhance efficiency and maintain therapeutic potency.
In Table 5, we provide a summary of the recommendations; the full explanatory text is included in Supplementary Explanations 5.
Limitations
The major limitation of this consensus-based guideline lies in the scarcity of high-quality evidence informing its discussions and recommendations. The current literature predominantly comprises preclinical and early-phase clinical trials, expert opinions and case reports or series. Consequently, for certain aspects, such as threshold definitions in phage quality control testing or PTMP dosing across different administration routes and clinical indications, precise values could not be specified, and recommendations were, instead, formulated based on the best available knowledge and expert consensus. In addition, as with any consensus-driven process, there is an inherent risk of suppressing minority perspectives and introducing bias related to participant selection and methodology. These challenges were addressed through a high degree of methodological transparency and precision, including the explicit indication of the strength of consensus for each recommendation. Furthermore, the guideline was developed by a multidisciplinary and international panel representing diverse areas of expertise and key stakeholder groups.
Conclusion
Healthcare professionals, pharmacists and patients are advocating for coherent, standardized frameworks to ensure the safe and effective integration of personalized phage therapy into pharmaceutical preparation and clinical practice. This guideline represents, to our knowledge, the first detailed and consensus-based statement on personalized phage therapy. It offers practical, inspection-ready standards that expand upon existing, less detailed guidance, supporting implementation in pharmaceutical and clinical settings. Its interdisciplinary and international development concept ensures broad applicability across medical specialties and healthcare systems worldwide. The final consensus statement provides over 60 recommendations and statements covering general principles, infrastructure, phage preparation and quality control, clinical application and research topics, which together form a comprehensive framework for establishing phage therapy as a legally compliant, high-quality and safe treatment option when antibiotics fail. Although intended for international application, we acknowledge that adaptation to the legal and regulatory nuances of local jurisdictions might still be needed. Moving forward, this guideline might serve as a foundation for global harmonization, regulatory refinement and the integration of phage therapy into routine patient care.
References
D’Herelle, F. Bacteriophage as a treatment in acute medical and surgical infections. Bull. N. Y. Acad. Med. 7, 329–348 (1931).
D’Herelle, F. On an invisible microbe antagonistic toward dysenteric bacilli: brief note by Mr. F. D’Herelle, presented by Mr. Roux. Res. Microbiol. 158, 553–554 (2007).
D’Herelle, F. Studies upon asiatic cholera. Yale J. Biol. Med. 1, 195–219 (1929).
Myelnikov, D. An alternative cure: the adoption and survival of bacteriophage therapy in the USSR, 1922−1955. J. Hist. Med. Allied Sci. 73, 385–411 (2018).
Bronfenbrenner, J. & Muckenfuss, R. Studies on the bacteriophage of d’Herelle: VIII. The mechanism of lysis of dead bacteria in the presence of bacteriophage. J. Exp. Med. 45, 887–909 (1927).
Chanishvili, N. Phage therapy—history from Twort and d’Herelle through Soviet experience to current approaches. Adv. Virus Res. 83, 3–40 (2012).
Clokie, M. R., Millard, A. D., Letarov, A. V. & Heaphy, S. Phages in nature. Bacteriophage 1, 31–45 (2011).
Suttle, C. A. Marine viruses—major players in the global ecosystem. Nat. Rev. Microbiol. 5, 801–812 (2007).
Al-Shayeb, B. et al. Clades of huge phages from across Earth’s ecosystems. Nature 578, 425–431 (2020).
Youngblut, N. D. et al. Vertebrate host phylogeny influences gut archaeal diversity. Nat. Microbiol. 6, 1443–1454 (2021).
Wielscher, M. et al. The phageome in normal and inflamed human skin. Sci. Adv. 9, eadg4015 (2023).
Shkoporov, A. N. & Hill, C. Bacteriophages of the human gut: the ‘known unknown’ of the microbiome. Cell Host Microbe 25, 195–209 (2019).
Cao, Z. et al. The gut virome: a new microbiome component in health and disease. EBioMedicine 81, 104113 (2022).
Howard-Varona, C., Hargreaves, K. R., Abedon, S. T. & Sullivan, M. B. Lysogeny in nature: mechanisms, impact and ecology of temperate phages. ISME J. 11, 1511–1520 (2017).
Mäntynen, S., Laanto, E., Oksanen, H. M., Poranen, M. M. & Díaz-Muñoz, S. L. Black box of phage-bacterium interactions: exploring alternative phage infection strategies. Open Biol. 11, 210188 (2021).
Phage therapy medicinal products (general chapter 5.31). In European Pharmacopoeia, 11th edn, Supplement 11.6. 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 (Council of Europe, 2024).
Pirnay, J. P. et al. Quality and safety requirements for sustainable phage therapy products. Pharm. Res. 32, 2173–2179 (2015).
Suh, G. A. et al. Considerations for the use of phage therapy in clinical practice. Antimicrob. Agents Chemother. 66, e0207121 (2022).
Liu, D. et al. The safety and toxicity of phage therapy: a review of animal and clinical studies. Viruses 13, 1268 (2021).
Uyttebroek, S. et al. Safety and efficacy of phage therapy in difficult-to-treat infections: a systematic review. Lancet Infect. Dis. 22, e208–e220 (2022).
Pirnay, J.-P. et al. Personalized bacteriophage therapy outcomes for 100 consecutive cases: a multicentre, multinational, retrospective observational study. Nat. Microbiol. 9, 1434–1453 (2024).
Stacey, H. J., De Soir, S. & Jones, J. D. The safety and efficacy of phage therapy: a systematic review of clinical and safety trials. Antibiotics (Basel) 11, 1340 (2022).
EudraLex − Volume 4 – Good Manufacturing Practice (GMP) guidelines. European Commission https://health.ec.europa.eu/medicinal-products/eudralex/eudralex-volume-4_en (2022).
Leitner, L. et al. Intravesical bacteriophages for treating urinary tract infections in patients undergoing transurethral resection of the prostate: a randomised, placebo-controlled, double-blind clinical trial. Lancet Infect. Dis. 21, 427–436 (2021).
Ooi, M. L. et al. Safety and tolerability of bacteriophage therapy for chronic rhinosinusitis due to Staphylococcus aureus. JAMA Otolaryngol. Head Neck Surg. 145, 723–729 (2019).
Jault, P. 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 Infect. Dis. 19, 35–45 (2019).
Wortelboer, K. et al. Phage-microbe dynamics after sterile faecal filtrate transplantation in individuals with metabolic syndrome: a double-blind, randomised, placebo-controlled clinical trial assessing efficacy and safety. Nat. Commun. 14, 5600 (2023).
Sarker, S. A. et al. Oral phage therapy of acute bacterial diarrhea with two coliphage preparations: a randomized trial in children from Bangladesh. EBioMedicine 4, 124–137 (2016).
Rhoads, D. D. et al. Bacteriophage therapy of venous leg ulcers in humans: results of a phase I safety trial. J. Wound Care 18, 237–238, 240−243 (2009).
Nir-Paz, R. et al. Randomized double-blind study on safety and tolerability of TP-102 phage cocktail in patients with infected and non-infected diabetic foot ulcers. Med 6, 100565 (2025).
Van Nieuwenhuyse, B. et al. A case of in situ phage therapy against Staphylococcus aureus in a bone allograft polymicrobial biofilm infection: outcomes and phage-antibiotic interactions. Viruses 13, 1898 (2021).
Van Nieuwenhuyse, B. et al. Case report: Personalized triple phage-antibiotic combination therapy to rescue necrotizing fasciitis caused by Panton-Valentine leukocidin-producing MRSA in a 12-year-old boy. Front. Cell. Infect. Microbiol. 14, 1354681 (2024).
Chan, B. K. et al. Personalized inhaled bacteriophage therapy for treatment of multidrug-resistant Pseudomonas aeruginosa in cystic fibrosis. Nat. Med. 31, 1494–1501 (2025).
Rubalskii, E. et al. Bacteriophage therapy for critical infections related to cardiothoracic surgery. Antibiotics (Basel) 9, 232 (2020).
Tkhilaishvili, T. et al. Successful case of adjunctive intravenous bacteriophage therapy to treat left ventricular assist device infection. J. Infect. 83, e1–e3 (2021).
Alt, V. et al. Case report: Local bacteriophage therapy for fracture-related infection with polymicrobial multi-resistant bacteria: hydrogel application and postoperative phage analysis through metagenomic sequencing. Front. Med. (Lausanne) 11, 1428432 (2024).
Tkhilaishvili, T., Winkler, T., Müller, M., Perka, C. & Trampuz, A. Bacteriophages as adjuvant to antibiotics for the treatment of periprosthetic joint infection caused by multidrug-resistant Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 64, e00924-19 (2019).
Paul, K. et al. Bacteriophage rescue therapy of a vancomycin-resistant Enterococcus faecium infection in a one-year-old child following a third liver transplantation. Viruses 13, 1785 (2021).
Vogt, D. et al. [Beyond antibiotic therapy - Future antiinfective strategies - Update 2017]. Unfallchirurg 120, 573–584 (2017).
McCallin, S., Sacher, J. C., Zheng, J. & Chan, B. K. Current state of compassionate phage therapy. Viruses 11, 343 (2019).
Doub, J. B. et al. Salphage: salvage bacteriophage therapy for a recalcitrant Klebsiella pneumoniae prosthetic shoulder infection—a case report. Acta Orthop. 93, 756–759 (2022).
Ferry, T. et al. Case report: Arthroscopic ‘debridement antibiotics and implant retention’ with local injection of personalized phage therapy to salvage a relapsing Pseudomonas aeruginosa prosthetic knee infection. Front. Med. (Lausanne) 8, 569159 (2021).
Doub, J. B., Ng, V. Y., Wilson, E., Corsini, L. & Chan, B. K. Successful treatment of a recalcitrant staphylococcus epidermidis prosthetic knee infection with intraoperative bacteriophage therapy. Pharmaceuticals (Basel) 14, 231 (2021).
Püschel, A., Skusa, R., Bollensdorf, A. & Gross, J. Local treatment of driveline infection with bacteriophages. Antibiotics (Basel) 11, 1310 (2022).
Popescu, M., Van Belleghem, J. D., Khosravi, A. & Bollyky, P. L. Bacteriophages and the immune system. Annu. Rev. Virol. 8, 415–435 (2021).
Van Belleghem, J. D., Dąbrowska, K., Vaneechoutte, M., Barr, J. J. & Bollyky, P. L. Interactions between bacteriophage, bacteria, and the mammalian immune system. Viruses 11, 10 (2018).
Sweere, J. M. et al. Bacteriophage trigger antiviral immunity and prevent clearance of bacterial infection. Science 363, eaat9691 (2019).
Górski, A. et al. Phages and immunomodulation. Future Microbiol. 12, 905–914 (2017).
Górski, A., Międzybrodzki, R., Jończyk-Matysiak, E., Kniotek, M. & Letkiewicz, S. Therapeutic phages as modulators of the immune response: practical implications. Clin. Infect. Dis. 77, S433–S439 (2023).
Górski, A., Międzybrodzki, R., Jończyk-Matysiak, E., Żaczek, M. & Borysowski, J. Phage-specific diverse effects of bacterial viruses on the immune system. Future Microbiol. 14, 1171–1174 (2019).
Górski, A. et al. Phage as a modulator of immune responses: practical implications for phage therapy. Adv. Virus Res. 83, 41–71 (2012).
Dąbrowska, K. Interaction of bacteriophages with the immune system: induction of bacteriophage-specific antibodies. Methods Mol. Biol. 1693, 139–150 (2018).
Dabrowska, K., Switała-Jeleń, K., Opolski, A. & Górski, A. Possible association between phages, Hoc protein, and the immune system. Arch. Virol. 151, 209–215 (2006).
Zhang, T. et al. A bacterial immunity protein directly senses two disparate phage proteins. Nature 635, 728–735 (2024).
Strathdee, S. A., Hatfull, G. F., Mutalik, V. K. & Schooley, R. T. Phage therapy: from biological mechanisms to future directions. Cell 186, 17–31 (2023).
Mitropoulou, G. et al. Phage therapy for pulmonary infections: lessons from clinical experiences and key considerations. Eur. Respir. Rev. 31, 220121 (2022).
Międzybrodzki, R. et al. Clinical aspects of phage therapy. Adv. Virus Res. 83, 73–121 (2012).
Aslam, S. Bacteriophage therapy as a treatment option for transplant infections. Curr. Opin. Infect. Dis. 33, 298–303 (2020).
Borysowski, J. & Górski, A. Is phage therapy acceptable in the immunocompromised host? Int. J. Infect. Dis. 12, 466–471 (2008).
Van Nieuwenhuyse, B. et al. Bacteriophage-antibiotic combination therapy against extensively drug-resistant Pseudomonas aeruginosa infection to allow liver transplantation in a toddler. Nat. Commun. 13, 5725 (2022).
Dedrick, R. M. et al. Phage therapy of mycobacterium infections: compassionate use of phages in 20 patients with drug-resistant mycobacterial disease. Clin. Infect. Dis. 76, 103–112 (2023).
Howard-Jones, A. R., Iredell, J. R. & Khatami, A. Phage therapy in pediatrics: the way forward for difficult-to-treat infections? Expert Rev. Anti Infect. Ther. 20, 487–491 (2022).
Dedrick, R. M. et al. Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus. Nat. Med. 25, 730–733 (2019).
Khatami, A. et al. Bacterial lysis, autophagy and innate immune responses during adjunctive phage therapy in a child. EMBO Mol. Med. 13, e13936 (2021).
Lebeaux, D. et al. A case of phage therapy against pandrug-resistant Achromobacter xylosoxidans in a 12-year-old lung-transplanted cystic fibrosis patient. Viruses 13, 60 (2021).
Gainey, A. B. et al. Combining bacteriophages with cefiderocol and meropenem/vaborbactam to treat a pan-drug resistant Achromobacter species infection in a pediatric cystic fibrosis patient. Pediatr. Pulmonol. 55, 2990–2994 (2020).
Duplessis, C. et al. Refractory Pseudomonas bacteremia in a 2-year-old sterilized by bacteriophage therapy. J. Pediatric Infect. Dis. Soc. 7, 253–256 (2018).
Fortuna, W., Miedzybrodzki, R., Weber-Dabrowska, B. & Górski, A. Bacteriophage therapy in children: facts and prospects. Med. Sci. Monit. 14, Ra126–Ra132 (2008).
Uhr, J. W., Dancis, J. & Finkelstein, M. S. Passage of bacteriophage phi X 174 across the placenta in guinea pigs. Proc. Soc. Exp. Biol. Med. 113, 391–394 (1963).
Kulangara, A. C. & Sellers, M. I. Passage of bacteriophages from mother to foetus in the rat. Proc. Soc. Exp. Biol. Med. 101, 207–211 (1959).
Srivastava, A. S., Chauhan, D. P. & Carrier, E. In utero detection of T7 phage after systemic administration to pregnant mice. Biotechniques 37, 81–83 (2004).
Young, G. R. et al. Optimisation and application of a novel method to identify bacteriophages in maternal milk and infant stool identifies host-phage communities within preterm infant gut. Front. Pediatr. 10, 856520 (2022).
Furfaro, L. L., Chang, B. J. & Payne, M. S. Applications for bacteriophage therapy during pregnancy and the perinatal period. Front. Microbiol. 8, 2660 (2017).
Shamash, M. & Maurice, C. F. Phages in the infant gut: a framework for virome development during early life. ISME J. 16, 323–330 (2022).
Ligonenko, O. V. et al. [Application of bacteriophages in the complex treatment of shotgun wounds of soft tissues in patients suffering from multiple antibiotic allergies]. Klin. Khir. 65−66 (2015).
Sakandelidze, V. M. [The combined use of specific phages and antibiotics in different infectious allergoses]. Vrach. Delo. 60−63 (1991).
European Committee on Antimicrobial Susceptibility Testing. EUCAST https://www.eucast.org/ast-of-phages (2026).
Phagistry. Registry for patients receiving phage therapy. https://www.phagistry.org (2026).
Nick, J. A. et al. Host and pathogen response to bacteriophage engineered against Mycobacterium abscessus lung infection. Cell 185, 1860–1874 (2022).
Bretaudeau, L., Tremblais, K., Aubrit, F., Meichenin, M. & Arnaud, I. Good Manufacturing Practice (GMP) compliance for phage therapy medicinal products. Front. Microbiol. 11, 1161 (2020).
Hietala, V., Horsma-Heikkinen, J., Carron, A., Skurnik, M. & Kiljunen, S. The removal of endo- and enterotoxins from bacteriophage preparations. Front. Microbiol. 10, 1674 (2019).
Van Belleghem, J. D., Merabishvili, M., Vergauwen, B., Lavigne, R. & Vaneechoutte, M. A comparative study of different strategies for removal of endotoxins from bacteriophage preparations. J. Microbiol. Methods 132, 153–159 (2017).
Merabishvili, M. et al. Quality-controlled small-scale production of a well-defined bacteriophage cocktail for use in human clinical trials. PLoS ONE 4, e4944 (2009).
Luong, T., Salabarria, A. C., Edwards, R. A. & Roach, D. R. Standardized bacteriophage purification for personalized phage therapy. Nat. Protoc. 15, 2867–2890 (2020).
Concept paper on the establishment of a guideline on the development and manufacture of human medicinal products specifically designed for phage therapy. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-quality-safety-and-efficacy-veterinary-medicinal-products-specifically-designed-phage-therapy_en.pdf (European Medicines Agency, 2023).
Pirnay, J. P. et al. The magistral phage. Viruses 10, 64 (2018).
Moraes de Souza, C., Tanir, T., Orellana, M., Escalante, A. & Koeris, M. S. Manufacturing bacteriophages (part 2 of 2): formulation, analytics and quality control considerations. Pharmaceuticals (Basel) 14, 895 (2021).
Rosner, D. & Clark, J. Formulations for bacteriophage therapy and the potential uses of immobilization. Pharmaceuticals (Basel) 14, 359 (2021).
Flint, R. et al. Stability considerations for bacteriophages in liquid formulations designed for nebulization. Cells 12, 2057 (2023).
Winzig, F. et al. Inhaled bacteriophage therapy for multi-drug resistant Achromobacter. Yale J. Biol. Med. 95, 413–427 (2022).
Malik, D. J. et al. Formulation, stabilisation and encapsulation of bacteriophage for phage therapy. Adv. Colloid. Interface Sci. 249, 100–133 (2017).
Karthika, C., Malligarjunan, N., Pandian, S. K. & Gowrishankar, S. Chitosan-encapsulated bacteriophage cocktail as promising oral delivery system to surpass gastrointestinal infection caused by Klebsiella aerogenes. Int. J. Biol. Macromol. 292, 139236 (2025).
Barros, J. A. R. et al. Encapsulated bacteriophages in alginate-nanohydroxyapatite hydrogel as a novel delivery system to prevent orthopedic implant-associated infections. Nanomedicine 24, 102145 (2020).
Colom, J. et al. Microencapsulation with alginate/CaCO3: a strategy for improved phage therapy. Sci. Rep. 7, 41441 (2017).
Ahmadi, H., Wang, Q., Lim, L. T. & Balamurugan, S. Encapsulation of Listeriaphage A511 by alginate to improve its thermal stability. Methods Mol. Biol. 1681, 89–95 (2018).
Kielholz, T., Rohde, F., Jung, N. & Windbergs, M. Bacteriophage-loaded functional nanofibers for treatment of P. aeruginosa and S. aureus wound infections. Sci. Rep. 13, 8330 (2023).
Cinquerrui, S., Mancuso, F., Vladisavljević, G. T., Bakker, S. E. & Malik, D. J. Nanoencapsulation of bacteriophages in liposomes prepared using microfluidic hydrodynamic flow focusing. Front. Microbiol. 9, 2172 (2018).
Moghtader, F., Solakoglu, S. & Piskin, E. Alginate- and chitosan-modified gelatin hydrogel microbeads for delivery of E. coli phages. Gels 10, 244 (2024).
Mohan, N., Bosco, K., Peter, A., Abhitha, K. & Bhat, S. G. Bacteriophage entrapment strategies for the treatment of chronic wound infections: a comprehensive review. Arch. Microbiol. 206, 443 (2024).
Mary, A. S. et al. Formulation of dual-functional nonionic cetomacrogol creams incorporated with bacteriophage and human platelet lysate for effective targeting of MDR P. aeruginosa and enhanced wound healing. ACS Appl. Bio. Mater. 7, 6583–6593 (2024).
Chen, B. et al. Combination of bacteriophages and vancomycin in a co-delivery hydrogel for localized treatment of fracture-related infections. NPJ Biofilms Microbiomes 10, 77 (2024).
Coleman, H. J. et al. Formulation of three tailed bacteriophages by spray-drying and atomic layer deposition for thermal stability and controlled release. J. Pharm. Sci. 113, 3238–3245 (2024).
Passerini, M., Petri, F. & Suh, G. A. Phage therapy for cardiac implantable electronic devices and vascular grafts: a targeted literature review. Pathogens 13, 424 (2024).
Rojas, S. V. et al. Bacteriophage-enriched galenic for intrapericardial ventricular assist device infection. Antibiotics (Basel) 11, 602 (2022).
European Commission. Guideline on the readability of the labelling and package leaflet of medicinal products for human use. European Commission https://health.ec.europa.eu/system/files/2016-11/2009_01_12_readability_guideline_final_en_0.pdf (2009).
US Food & Drug Administration. Bacterial Endotoxins/Pyrogens. FDA https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-technical-guides/bacterial-endotoxinspyrogens (2014).
Pyrogenicity (general chapter 5.1.13). In European Pharmacopoeia 11th edn (European Directorate for the Quality of Medicines & HealthCare, 2025).
Jończyk, E., Kłak, M., Międzybrodzki, R. & Górski, A. The influence of external factors on bacteriophages—review. Folia Microbiol. (Praha) 56, 191–200 (2011).
Wdowiak, M., Paczesny, J. & Raza, S. Enhancing the stability of bacteriophages using physical, chemical, and nano-based approaches: a review. Pharmaceutics 14, 1936 (2022).
Pirnay, J. P., Merabishvili, M., Van Raemdonck, H., De Vos, D. & Verbeken, G. Bacteriophage production in compliance with regulatory requirements. Methods Mol. Biol. 1693, 233–252 (2018).
König, H. & Sauter, A. Bakteriophagen in Medizin, Land- und Lebensmittelwirtschaft – Anwendungsperspektiven, Innovations- und Regulierungsfragen. Innovationsanalyse. KIT https://publikationen.bibliothek.kit.edu/1000160512 (2023).
Merabishvili, M., Pirnay, J. P. & De Vos, D. Guidelines to compose an ideal bacteriophage cocktail. Methods Mol. Biol. 1693, 99–110 (2018).
Molina, F., Menor-Flores, M., Fernández, L., Vega-Rodríguez, M. A. & García, P. Systematic analysis of putative phage-phage interactions on minimum-sized phage cocktails. Sci. Rep. 12, 2458 (2022).
Kim, M. K. et al. A blueprint for broadly effective bacteriophage-antibiotic cocktails against bacterial infections. Nat. Commun. 15, 9987 (2024).
Chan, B. K., Abedon, S. T. & Loc-Carrillo, C. Phage cocktails and the future of phage therapy. Future Microbiol. 8, 769–783 (2013).
Rotman, S. G. et al. Local bacteriophage delivery for treatment and prevention of bacterial infections. Front. Microbiol. 11, 538060 (2020).
Niu, Y. D. et al. Efficacy of individual bacteriophages does not predict efficacy of bacteriophage cocktails for control of Escherichia coli O157. Front. Microbiol. 12, 616712 (2021).
Würstle, S. et al. Optimized preparation pipeline for emergency phage therapy against Pseudomonas aeruginosa at Yale University. Sci. Rep. 14, 2657 (2024).
Torres-Barceló, C., Turner, P. E. & Buckling, A. Mitigation of evolved bacterial resistance to phage therapy. Curr. Opin. Virol. 53, 101201 (2022).
Hall, A. R., De Vos, D., Friman, V. P., Pirnay, J. P. & Buckling, A. Effects of sequential and simultaneous applications of bacteriophages on populations of Pseudomonas aeruginosa in vitro and in wax moth larvae. Appl. Environ. Microbiol. 78, 5646–5652 (2012).
Burmeister, A. R. & Turner, P. E. Trading-off and trading-up in the world of bacteria-phage evolution. Curr. Biol. 30, R1120–R1124 (2020).
Chan, B. K. et al. Phage selection restores antibiotic sensitivity in MDR Pseudomonas aeruginosa. Sci. Rep. 6, 26717 (2016).
Gurney, J. et al. Phage steering of antibiotic-resistance evolution in the bacterial pathogen, Pseudomonas aeruginosa. Evol. Med. Public Health 2020, 148–157 (2020).
Oromí-Bosch, A., Antani, J. D. & Turner, P. E. Developing phage therapy that overcomes the evolution of bacterial resistance. Annu. Rev. Virol. 10, 503–524 (2023).
Kortright, K. E., Chan, B. K., Koff, J. L. & Turner, P. E. Phage therapy: a renewed approach to combat antibiotic-resistant bacteria. Cell Host Microbe 25, 219–232 (2019).
Kunisch, F. et al. Targeting Pseudomonas aeruginosa biofilm with an evolutionary trained bacteriophage cocktail exploiting phage resistance trade-offs. Nat. Commun. 15, 8572 (2024).
Bernabéu-Gimeno, M. et al. Neutralizing antibodies after nebulized phage therapy in cystic fibrosis patients. Med 5, 1096–1111 (2024).
Międzybrodzki, R. et al. Means to facilitate the overcoming of gastric juice barrier by a therapeutic staphylococcal bacteriophage A5/80. Front. Microbiol. 8, 467 (2017).
Le Guellec, S. et al. Administration of bacteriophages via nebulization during mechanical ventilation: in vitro study and lung deposition in macaques. Viruses 15, 602 (2023).
Richter, Ł et al. Adsorption of bacteriophages on polypropylene labware affects the reproducibility of phage research. Sci. Rep. 11, 7387 (2021).
Wright, A., Hawkins, C. H., Anggård, E. E. & Harper, D. R. A controlled clinical trial of a therapeutic bacteriophage preparation in chronic otitis due to antibiotic-resistant Pseudomonas aeruginosa; a preliminary report of efficacy. Clin. Otolaryngol. 34, 349–357 (2009).
Kim, P. 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. 24, 1319–1332 (2024).
Koncz, M. et al. Genomic surveillance as a scalable framework for precision phage therapy against antibiotic-resistant pathogens. Cell 187, 5901–5918 (2024).
Parmar, K. et al. Interlaboratory comparison of Pseudomonas aeruginosa phage susceptibility testing. J. Clin. Microbiol. 61, e0061423 (2023).
Kolenda, C., Jourdan, J., Roussel-Gaillard, T., Medina, M. & Laurent, F. Phage susceptibility testing methods or ‘phagograms’: where do we stand and where should we go? J. Antimicrob. Chemother. 79, 2742–2749 (2024).
Khan Mirzaei, M. & Nilsson, A. S. Isolation of phages for phage therapy: a comparison of spot tests and efficiency of plating analyses for determination of host range and efficacy. PLoS ONE 10, e0118557 (2015).
Kunz Coyne, A. J. et al. Exploring synergistic and antagonistic interactions in phage-antibiotic combinations against ESKAPE pathogens. Microbiol. Spectr. 12, e0042724 (2024).
Gordillo Altamirano, F. L. et al. Phage-antibiotic combination is a superior treatment against Acinetobacter baumanniiin a preclinical study. EBioMedicine 80, 104045 (2022).
Ma, L., Green, S. I., Trautner, B. W., Ramig, R. F. & Maresso, A. W. Metals enhance the killing of bacteria by bacteriophage in human blood. Sci. Rep. 8, 2326 (2018).
Youssef, O. et al. Impact of the calcium concentration on the efficacy of phage phiIPLA-RODI, LysRODIΔAmi and nisin for the elimination of Staphylococcus aureus during lab-scale cheese production. Int. J. Food Microbiol. 399, 110227 (2023).
Bichet, M. C. et al. Bacteriophage uptake by mammalian cell layers represents a potential sink that may impact phage therapy. iScience 24, 102287 (2021).
Dedrick, R. M. et al. Potent antibody-mediated neutralization limits bacteriophage treatment of a pulmonary Mycobacterium abscessus infection. Nat. Med. 27, 1357–1361 (2021).
Żaczek, M. et al. Antibody production in response to staphylococcal MS-1 phage cocktail in patients undergoing phage therapy. Front. Microbiol. 7, 1681 (2016).
Loh, B. et al. Encapsulation and delivery of therapeutic phages. Appl. Environ. Microbiol. 87, e01979-20 (2021).
Vogele, K., Falgenhauer, E., von Schönberg, S., Simmel, F. C. & Pirzer, T. Small antisense DNA-based gene silencing enables cell-free bacteriophage manipulation and genome replication. ACS Synth. Biol. 10, 459–465 (2021).
Levrier, A. et al. PHEIGES: all-cell-free phage synthesis and selection from engineered genomes. Nat. Commun. 15, 2223 (2024).
Emslander, Q. et al. Cell-free production of personalized therapeutic phages targeting multidrug-resistant bacteria. Cell Chem. Biol. 29, 1434–1445 (2022).
Acknowledgements
We thank the AWMF, in particular I. Kopp and M. Nothacker, for providing methodological guidance and facilitating the consensus conferences as neutral guideline experts and moderators. We also thank L. Weipert for serving as the neutral reviewer for all declarations of conflicts of interest and L. Holt and D. Cartolano for their coordination support.
We thank the external reviewers for their thorough review and valuable support of the guideline recommendations: T. Faltus, P. Ruth, H. Blume, M. Clokie, R. Nakayinga, S. Lee, R. Nir-Paz, G. Suh, J. Iredell and G. J. German. We gratefully acknowledge the endorsing societies and organizations, and their designated representatives, for their careful review and endorsement of the recommendations presented in this guideline: Phage Directory (representative: J. Sacher, Co-founder), PhageAfrica (Africa Phage Forum, representative: E. Nnadi), Infectious Diseases Society of America (IDSA) (representative: IDSA Practice Guidelines Team), Japanese Association for Infectious Diseases (JAID) (representative: T. Matsumoto, President), Latvian Antimicrobial Resistance Competence Center (representative: U. Dumpis, Head of the Latvian National AMR Competence Center), ESCMID Study Group for Non-Traditional Antibacterial Therapy (ESGNTA, representative: R. Nir-Paz, Chair of the Executive Committee), European Committee on Antimicrobial Susceptibility Testing (EUCAST) Phage Susceptibility Testing Subcommittee (EUCAST PST-SC representative: F. Laurent, Chair of the EUCAST PST-SC), European Society for Pediatric Infectious Diseases (ESPID) (representative: A. Warris, President) and the Australasian Society for Infectious Diseases (ASID) (representative: I. Kourtis, Chief Executive Officer). The endorsement process followed the respective procedures and requirements of each society and organization.
To enhance efficiency and quality, this guideline was prepared with the assistance of generative AI tools, specifically, ChatGPT (GPT-4 and GPT-5), DeepL (version 24.2.2) and Claude (Opus 5). AI tools were used to improve comprehension of the text and to refine the English language. Nevertheless, the proposal was revised, reviewed and edited by the authors, who take full responsibility for the content.
Medicine is subject to an ongoing development process, so all information, especially regarding diagnostic and therapeutic procedures, can only reflect the knowledge available at the time of the publication of the guideline.
Any discrepancies should be reported to the DGI. Responsibility for all diagnostic and therapeutic measures, including medication selection, administration and dosage, remains with the user of this guideline.
Registered trademarks (protected product names) are not specifically highlighted in this guideline. Therefore, the absence of such a notice should not be interpreted as indicating that the name is a free product name. Any use outside the scope of the Copyright Act and the contracts with the participating societies without the written consent of the DGI is prohibited and punishable.
Funding
The development of the guideline was carried out with editorial independence. The DGI financed the AWMF moderation of the online consensus conferences but did not influence any of the guideline content. No financial contributions from third parties were made. Steering committee members, mandate holders and deputies, invited experts, patient representatives and reviewers worked exclusively on a voluntary basis.
Author information
Authors and Affiliations
Consortia
Contributions
S.W., S.L.J., M.J.G.T.V. and A.Y.C. coordinated the structured guideline process in accordance with the framework of the AWMF in Germany and drafted the manuscript. All authors, except the external reviewers (T. Faltus, P.R. and H.B.), were actively involved in the subgroup work and the preparation and/or discussions of the six consensus conferences and contributed to the manuscript. All authors reviewed and approved the final version of the manuscript.
Corresponding author
Ethics declarations
Competing interests
The competing interests declared below reflect the authors’ disclosures during the development and up to the endorsement of this guideline by the participating societies. S.W. declares receiving third-party funding for research projects to the author’s institution, with no direct personal payment, and being a founding member of Phage4-1Health (unpaid position) as well as elected member of the steering committee of the PhageNET DZIF (unpaid). S.L.J. received a maternity leave stipend from the German Center for Infection Research and a grant from the Fraunhofer Thera Nova Program as well as travel support to the ESCMID phage course in Lyon 2024 and receipt of equipment from the German Collection of Microorganisms and Cell Cultures (DSMZ). H.L. is an inventor on patents relating to Bacterial Vector (publication number: 20080112928), Pharmaceutical Composition for Tumor Treatment (publication number: 20100086557), Tumor-Specific Bacterial Promoter Elements (publication number: 20120244621) and Codon Optimization (publication number: 20190325989). P.J.C. reports institutional research funding through the PhageSafety (Institut Pasteur Network Grant) and EPHICACI (FWO Grant) research projects and serving as an unpaid member of the KLEOPATRA Advisory Board (JPIAMR grant), an unpaid lead of the EDQM Working Group on Bacteriophages, an unpaid member of the EUCAST Phage Susceptibility Testing (EUCAST-PST) Subcommittee and an unpaid board member of the Belgian Society for Viruses of Microbes. J.P.P. is employed by the Belgian Defense as statutory officer, and he received travel support (including registration fees, flights and accommodation) from several conference organizers and academic institutions, including the Global AMR R&D Hub, Riga Stradiņš University, Argomenti di Malattie Infettive e Tropicali (AMIT), the Phage Therapy Congress and Lund University, for participation in scientific meetings and conferences. J.P.P. serves as unpaid Secretary of P-H-A-G-E.org; unpaid Science Officer of the ESCMID Study Group for Non-Traditional Antibacterial Therapy (ESGNTA); an unpaid member of the European Medicines Agency (EMA) Novel Therapies and Technologies Working Party Operational Expert Group on Bacteriophages, where he contributes to the development of guidance on the quality, safety and efficacy of bacteriophages as veterinary medicines; and as team leader of the NATO Science and Technology Organization project Reintroduction of Phage Therapy in Military Medicine. In addition, J.P.P. serves as Vice Chair Cross Reader for European Commission Horizon 2020 and Horizon Europe calls (paid). M.d.J. received a postdoctoral research grant through the SAPHETY project. M.d.J. participated in the development of these guidelines while employed at Sciensano and has been employed by Rime Bioinformatics, a French start-up specializing in phage genomics, since November 2024. S.M. reports academic research funding from The LOOP Zurich (mTORUS project), the University of Zurich Postdoctoral Grant, the Marie Skłodowska-Curie Innovative Training Network (VIROINF) and the Swiss National Science Foundation (SPIRIT project). S.M.C. received travel support to attend the IndoSwiss AMR Dialogue (Bangalore, 2023). S.M.C. serves as an unpaid advisory board member of the EPICACY project, an unpaid Executive Board member of the ESCMID Study Group for Non-Traditional Antibacterial Therapy (ESGNTA) and the International Society for Viruses of Microbes (ISVM) and as unpaid Project Coordinator of International Phagistry. L.L. reports research funding from The LOOP Zurich (mTORUS 2022) and received travel support to attend the 16th Annual Meeting of the German Society for Environmental Dentistry. C.W. reports research grants and consulting fees from Solventum, Mölnlycke, Delta G and Avaris. C.W. also received honoraria for lectures and presentations from Solventum and Mölnlycke. S.L. is a member of the PhageNET DZIF Steering Committee (unpaid). E.A.I. reports institutional research funding from the German Federal Ministry of Education and Research (BMBF), MetaSystems Hard & Software GmbH and the Federal State of Mecklenburg-Vorpommern (EFRE). E.A.I. receives inventor remuneration from the University of Münster for patents licensed to Bruker. E.A.I. received personal honoraria for lectures and presentations from Shionogi, Pfizer and BD Biosciences, including travel support from Pfizer and BD Biosciences. E.A.I. also received personal honoraria for serving on the expert board of the Institute for Quality Assurance and Transparency in Healthcare (IQTIG) for the quality assurance program on sepsis diagnosis, treatment and follow-up. M.W. reports research grants from the German Federal Ministry of Education and Research (BMBF), the German Research Foundation (DFG), the Federal Joint Committee (G-BA), the German Federal Ministry of Health (BMG) as well as Biotest, Pantherna and Aptarion. M.W. received consulting fees from Biotest, Pantherna and Aptarion and personal honoraria for lectures and presentations from AstraZeneca, Chiesi, Insmed, Gilead, Pfizer and Boehringer Ingelheim. T. Faltus received personal remuneration from Springer Nature for authoring a review article on phage therapeutics and pharmaceutical legislation. P.R. reports grants from the DFG and received personal honoraria for lectures and presentations from AVOXA, PHOENIX Pharma and the German Pharmaceutical Society (DPhG) and travel support from AVOXA. P.R. serves in unpaid advisory roles on the Scientific Advisory Board of the Federal Chamber of Pharmacists (BAK), the Federal Institute for Drugs and Medical Devices (BfArM) and the Drug Commission of German Pharmacists (AMK). H.F. serves as an unpaid member of the Federal Weekly Conference on the Epidemiological Situation (EpiLag) at the Robert Koch Institute (RKI) and the Federal Working Group on Infection Surveillance (BLAG) at the RKI. H.F. is President of the German Association for the Control of Virus Diseases (DVV), a board member of the German Society for Hygiene and Microbiology (DGHM) and advisory board member of the German Society for Virology (GfV), and the State Representative for Schleswig-Holstein of the German Medical Association for Information Technology, Medical Informatics and eHealth (BÄMI). M.W.P. serves as president for the Paul Ehrlich Society for Antiinfective Therapy (unpaid). U.M. received consulting fees and personal honoraria for lectures, presentations and educational activities from Austrianni. S.B. serves as an unpaid Speaker of the Special Interest Group ‘Microbial Viruses’ of the German Society for General and Applied Microbiology (VAAM). M.S. reports institutional research funding from Vertex Pharmaceuticals through an investigator-initiated research award. M.S. received consulting fees, personal honoraria for lectures, presentations and educational activities and travel support and served on advisory boards for Vertex Pharmaceuticals. M.S. serves as the President-Elect of the German Society for Pediatric Pulmonology (GPP) and as Chair of the German Cystic Fibrosis Research Council (FGM), both unpaid. J.B. reports research funding from the German Armed Forces CBRN Protection Program (B-Schutzprogramm) and the European Defence Fund (EDF) Resilience PHAGE project. J.J.B. received travel support from the EDF Resilience PHAGE project and serves in an unpaid leadership role within the EDF Resilience PHAGE consortium. M.K. received personal honoraria for lectures from the Medical Association of North Rhine (Ärztekammer Nordrhein) and the Academy for Infectious Medicine (Akademie für Infektionsmedizin e.V.). P.T. reports institutional research funding from the Howard Hughes Medical Institute, the Ralph & Marian Falk Medical Research Trust and the Colton Center for Autoimmunity. T. Ferry reports institutional research funding from PHAXIAM. T. Ferry serves as the unpaid Clinical Officer of the ESCMID Study Group for Non-Traditional Antibacterial Therapy (ESGNTA). M.J.G.T.V. reports research grants from Merck Sharp & Dohme, Heel, Roche and Tillotts. M.J.G.T.V. received consulting fees from Gilead, Tillotts, Pfizer, BIOASTER, GlaxoSmithKline, Ecraid, Eumedica, Bactolife and PAION. M.J.G.T.V. also received personal honoraria for lectures, presentations and educational activities from the Academy for Infectious Medicine (Akademie für Infektionsmedizin), AstraZeneca, bioMérieux, Biotest, COCS GmbH, the DGI, the European Society of Neurogastroenterology, the Falk Foundation, FomF GmbH, Gilead, GlaxoSmithKline, Helios Kliniken, the Hessian State Social Court (Hessisches Landessozialgericht), Infektio Forum, Janssen-Cilag, Klinikum Kassel, the State Medical Association of Hesse (Landesärztekammer Hessen), LMU Kliniken, Merck Sharp & Dohme, Pfizer, Streamed Up, St. Vincent Hospital and Tillotts. A.Y.C. reports institutional research funding from the German Center for Infection Research (DZIF) and the Federal Ministry of Education and Research (BMFTR). A.Y.C. received personal honoraria for lectures from Roland Berger, Goethe University Frankfurt and the Academy for Infectious Medicine (Akademie für Infektionsmedizin e.V.). A.Y.C. received travel grants from ESCMID (2024 and 2025) and the Federation of European Microbiological Societies (FEMS) (2023). A.Y.C. serves as the unpaid Scientific Secretary of the EUCAST Subcommittee on Phage Susceptibility Testing as well as elected member of the steering committee of the PhageNET DZIF (unpaid). A.Y.C. is a member of the DGI, the German Society of Internal Medicine (DGIM), the German Society for Hematology and Medical Oncology/Infectious Diseases Working Group (DGHO/AGIHO) and the ESCMID Study Group for Non-Traditional Antibacterial Therapy (ESGNTA). A.D., O.K., I.K., H.B., M.C., S.H., C.R., W.B., O.H., R.L.K., M.D., J.H., R.K. and B.C. declare no competing interests. An overview of the competing interests of the full guideline group ‘Personalized Bacteriophage Therapy’ of the Association of the Scientific Medical Societies in Germany is published in Supplementary File 1. The evaluation and management of competing interests is detailed in the section ‘Disclosure of interests and management of conflicts’ (Supplementary Methods).
Peer review
Peer review information
Nature Medicine thanks Jeremy Barr and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Joao Monteiro, in collaboration with the Nature Medicine team.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Supplementary Information (download PDF )
Supplementary Explanations; Supplementary Methods; Supplementary File 1. Summary of the declarations of conflicts of interest; Supplementary File 2. Template material transfer agreement; and Supplementary File 3. Template informed consent form for patients.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Würstle, S., Lieberknecht-Jouy, S.C., Düchting, A. et al. A consensus-based guideline for personalized bacteriophage therapy. Nat Med (2026). https://doi.org/10.1038/s41591-026-04654-6
Received:
Accepted:
Published:
Version of record:
DOI: https://doi.org/10.1038/s41591-026-04654-6