Bacteriophages have been applied therapeutically for more than a century for the management of bacterial infections in humans. Although their potential as a safe alternative or adjunct to antibiotics is well established, clinical success is difficult to predict from in vitro testing. There is currently no consensus on the optimal way to use them, nor are there any simple extrapolations from the use paradigms of conventional antibiotics. A rational approach to phage therapy requires informed phage selection and a comprehensive understanding of bacterial-phage-human host relationships and the management of bacterial and phage adaptations that occur in vivo. Phages may be used in ways that antibiotics are not and are a powerful approach for addressing the problem of antimicrobial resistance, not least because their optimal use requires a more thoughtful approach. In this Review, we explore key aspects of phage biology that underpin the effective use of phages for therapy. We outline clinical strategies for applying phages against a range of infections, highlighting their advantages and limitations. We then address challenges in production, scalability and regulation of phage preparations, identifying areas requiring further development. Finally, we discuss interactions between phages and the human immune system, and their importance for therapeutic success.

OBJECTIVE:Phage therapy is a promising tool to combat the global threat of antimicrobial resistance. Clinicians, as part of interdisciplinary teams, play an integral role in identifying patients for therapy, delivering phages, and monitoring treatment outcomes and safety. As such, in the context of rapidly evolving regulatory landscapes, clinician insight is crucial for advancement of phage therapy. In this study, we describe the first published international anonymized survey aimed at identifying attitudes and experiences of clinicians and healthcare professionals towards phage therapy. METHODS:We distributed the survey to participants in the Global Clinical Phage Rounds, a network of >300 phage clinicians, health professionals, and scientists, from October 15, 2024 - January 30, 2025. RESULTS:Thirty respondents representing North America, Europe, Oceania, Africa, and Asia completed the survey (response rate 9.6%). The majority of respondents were very well-informed about phage therapy and 93% would consider enrolling their patients in phage therapy randomized controlled trials. Respondents identified Pseudomonas aeruginosa, Klebsiella species, and Staphylococcus aureus as priority organisms and bone/joint, respiratory, and urinary tract infections as priority syndromes. Respondents had concerns about clinical use evidence, regulatory barriers, and accessing phage. Twenty respondents reported experience with phage therapy, so answered additional questions. These respondents acquired phages from sources like phage banks, industry, and importation from other countries. Respondents delivered phage therapy primarily in single-use cases via parenteral/intravenous, topical, or inhalation routes. Experienced respondents endorsed combinations of monitoring before, during, and/or after phage therapy. CONCLUSIONS:These results serve as a guiding initiative to improve phage therapy integration in healthcare.

BACKGROUND:Due to the rise in antimicrobial resistance, there has been an increased interest in phage therapy to treat multidrug-resistant infections. In Australia, phage therapy is predominantly used in small clinical studies or for compassionate use; however, despite its potential expansion in modern medicine, the perception of phage therapy among medical professionals remains largely unknown. METHODS:We conducted a national survey of Australian infectious diseases and clinical microbiology advanced trainees and specialists using an online mailing list to assess their knowledge, areas of interest, and concerns around the use of phage therapy in clinical practice in Australia; with 92 eligible respondents. RESULTS:Most respondents believed that the current national plan for controlling antimicrobial resistance is inadequate and that phage therapy may be an effective solution; with 87 (97%) indicating that they would consider using phage therapy meeting established guidelines for purity and safety. There was a preference for bespoke therapy, with Gram-negative pathogens highlighted as priority targets. Alongside the phage therapy delivery protocols, therapeutic phage monitoring was considered important. Cystic fibrosis, lung-infections, prosthetic device/related infections, and infections among patients following transplantation and/or immunosuppression were highly ranked in terms of priorities for clinical syndromes. Accessibility was highlighted as a barrier to phage therapy, specifically, timely access (n = 66; 72%) and logistics of phage procurement and administration (n = 64; 70%). CONCLUSIONS:These results suggest the support of phage therapy among infectious diseases and clinical microbiology advanced trainees and specialists in Australia, and highlights areas of focus and priority in order to advance phage therapy.

Cystic fibrosis (CF) is the most prevalent serious inherited disease in Australia, imposing significant health risks. CF is characterized by chronic lung inflammation and recurrent pulmonary infections that increase morbidity and premature mortality rates. The emergence of antimicrobial resistance (AMR) places further challenges on the treatment and management of CF, necessitating research into alternative strategies for treatment of bacterial infections. Bacteriophage therapy, involving bacterial-specific viruses, is a potential avenue for AMR infections in patients with CF. Existing literature supports the feasibility of phage therapy in CF but there has been a gap in investigating attitudes of the CF community including affected individuals and their caregivers, regarding phage therapy. Understanding perspectives and needs of the CF community is essential for successful implementation and acceptance of novel therapies including phage therapy. We conducted a survey that encompasses responses from 112 consumers from across Australia, comprising people living with CF (38.4%), parents of affected children (49.6%), carers (6.4%), and family members (3%). The findings showed a significant reliance on antibiotics with 51.4% requiring oral, 43.4% nebulized, and 11.4% intravenous antibiotics within the preceding 2 weeks. Respondents highlighted the availability of new treatments, duration of hospitalizations and costs associated with treatment as important priorities to address. Despite an awareness of phage therapy among 62.4% of respondents, 86.4% expressed interest in obtaining more information, primarily from medical staff (66.7%). Notably, 96.0% of respondents expressed willingness to participate in phage therapy trials. The results of this survey highlighted the CF community’s strong interest in advanced therapeutic approaches, specifically phage therapy. The findings reveal a notable recognition and acceptance of phage therapy as a viable treatment option for pulmonary infections associated with CF. This study addresses UN Sustainable Development Goal 3: Good Health and Wellbeing by advancing knowledge on alternative therapeutic strategies for managing AMR in CF. By exploring community attitudes towards bacteriophage therapy, the research promotes informed development and implementation of innovative, targeted treatments for CF-associated infections. These findings support the sustainable management of AMR, fostering better health outcomes and reducing reliance on traditional antibiotics, thereby contributing to long-term health resilience.

BACKGROUND:Concerns about the rise in antimicrobial resistance have led to renewed interest in phage therapy worldwide, but perceptions among relevant medical professionals in Korea remain largely unknown.MATERIALS AND METHODS:We conducted a semi-quantitative online survey to evaluate the Korean infectious disease specialists' perception of phage therapy.RESULTS:We sent out the link to the questionnaire to 380 subjects and received 91 replies, with 90/91 respondents identifying as Korean infectious diseases specialists or trainees. Ten out of 91 (11.0%) respondents scored themselves as well-informed about phage therapy. The majority (93.4%) of respondents would consider using phage therapy if the safety of the phage formulation is guaranteed, and 80% of respondents would consider participating in clinical trials with phage therapy given adequate support. The biggest concern was uncertainty about safety (73.6%) and efficacy (65.9%). Acinetobacter baumannii was ranked as a high priority for phage therapy research, as were bone and joint infections.CONCLUSION:Korean infectious diseases specialists are receptive to phage therapy, but a better understanding of safety, efficacy and clinical trials are warranted to progress phage therapy within the Korean healthcare system.

There is a growing appreciation that the direct interaction between bacteriophages and the mammalian host can facilitate diverse and unexplored symbioses. Yet the impact these bacteriophages may have on mammalian cellular and immunological processes is poorly understood. Here, we applied highly purified phage T4, free from bacterial by-products and endotoxins to mammalian cells and analyzed the cellular responses using luciferase reporter and antibody microarray assays. Phage preparations were applied in vitro to either A549 lung epithelial cells, MDCK-I kidney cells, or primary mouse bone marrow derived macrophages with the phage-free supernatant serving as a comparative control. Highly purified T4 phages were rapidly internalized by mammalian cells and accumulated within macropinosomes but did not activate the inflammatory DNA response TLR9 or cGAS-STING pathways. Following 8 hours of incubation with T4 phage, whole cell lysates were analyzed via antibody microarray that detected expression and phosphorylation levels of human signaling proteins. T4 phage application led to the activation of AKT-dependent pathways, resulting in an increase in cell metabolism, survival, and actin reorganization, the last being critical for macropinocytosis and potentially regulating a positive feedback loop to drive further phage internalization. T4 phages additionally down-regulated CDK1 and its downstream effectors, leading to an inhibition of cell cycle progression and an increase in cellular growth through a prolonged G1 phase. These interactions demonstrate that highly purified T4 phages do not activate DNA-mediated inflammatory pathways but do trigger protein phosphorylation cascades that promote cellular growth and survival. We conclude that mammalian cells are internalizing bacteriophages as a resource to promote cellular growth and metabolism.

Background: A growing number of compassionate phage therapy cases were reported in the last decade, with a limited number of clinical trials conducted and few unsuccessful clinical trials reported. There is only a little evidence on the role of phages in refractory infections. Our objective here was to present the largest compassionate-use single-organism/phage case series in 16 patients with non-resolving Pseudomonas aeruginosa infections. Methods: We summarized clinical phage microbiology susceptibility data, administration protocol, clinical data, and outcomes of all cases treated with PASA16 phage. In all intravenous phage administrations, PASA16 phage was manufactured and provided pro bono by Adaptive Phage Therapeutics. PASA16 was administered intravenously, locally to infection site, or by topical use to 16 patients, with data available for 15 patients, mainly with osteoarticular and foreign-device-associated infections. Findings: A few minor side effects were noted, including elevated liver function enzymes and a transient reduction in white blood cell count. Good clinical outcome was documented in 13 out of 15 patients (86.6%). Two clinical failures were reported. The minimum therapy duration was 8 days with a once-to twice-daily regimen. Conclusions: PASA16 with antibiotics was found to be relatively successful in patients for whom traditional treatment approaches have failed previously. Such pre-phase-1 cohorts can outline potential clinical protocols and facilitate the design of future trials.

Distal hereditary motor neuropathies (dHMNs) are a group of inherited diseases involving the progressive, length-dependent axonal degeneration of the lower motor neurons. There are currently 29 reported causative genes and four disease loci implicated in dHMN. Despite the high genetic heterogeneity, mutations in the known genes account for less than 20% of dHMN cases, with the mutations identified predominantly being point mutations or indels. We have expanded the spectrum of dHMN mutations with the identification of a 1.35 Mb complex structural variation (SV) causing a form of autosomal dominant dHMN (DHMN1 OMIM %182906). Given the complex nature of SV mutations and the importance of studying pathogenic mechanisms in a neuronal setting, we generated a patient-derived DHMN1 motor neuron model harbouring the 1.35 Mb complex insertion. The DHMN1 complex insertion creates a duplicated copy of the first 10 exons of the ubiquitin-protein E3 ligase gene (UBE3C) and forms a novel gene-intergenic fusion sense transcript by incorporating a terminal pseudo-exon from intergenic sequence within the DHMN1 locus. The UBE3C intergenic fusion (UBE3C-IF) transcript does not undergo nonsense-mediated decay and results in a significant reduction of wild-type full-length UBE3C (UBE3C-WT) protein levels in DHMN1 iPSC-derived motor neurons. An engineered transgenic Caenorhabditis elegans model expressing the UBE3C-IF transcript in GABA-ergic motor neurons shows neuronal synaptic transmission deficits. Furthermore, the transgenic animals are susceptible to heat stress, which may implicate defective protein homeostasis underlying DHMN1 pathogenesis. Identification of the novel UBE3C-IF gene-intergenic fusion transcript in motor neurons highlights a potential new disease mechanism underlying axonal and motor neuron degeneration. These complementary models serve as a powerful paradigm for studying the DHMN1 complex SV and an invaluable tool for defining therapeutic targets for DHMN1. Cutrupi et al. describe the formation of a novel gene-intergenic fusion involving the UBE3C gene in patients with distal hereditary motor neuropathy 1 (DHMN1). The transcript (UBE3C-IF) results in decreased UBE3C protein levels in hiPSC motor neurons and causes synaptic transmission deficits and susceptibility to heat stress in C. elegans.

The escalating issue of multidrug-resistant (MDR) bacteria indicates the urgent need for new and effective strategies to combat this global health challenge. Here, we describe a new combinatorial approach that can be put forward for experimental therapy application against MDR bacteria. Specifically, we have developed a tri-system that includes the coadministration of two different membrane-disrupting-type antimicrobial agents─a synthetic antimicrobial polymer P and an antimicrobial peptide (AMP) colistin methanesulfonate (Col)─in conjunction with an antibiotic [doxycycline (Dox), rifampicin (Rif), or azithromycin (Azi)]. Traditionally, the administration of membrane-disrupting antimicrobial agents causes toxicity, but, in comparison, we demonstrated synergy and biocompatibility using this combinatorial approach. Checkerboard assays showed the occurrence of synergistic interactions in Col-Dox-P, Col-Rif-P, and Col-Azi-P tri-systems against wild-type and MDR Pseudomonas aeruginosa, with the Col-Dox-P system being the most effective. The ability to synergize thus enables the use of a lower dosage in combinations compared to the standalone agents. The tri-systems not only demonstrated bacteriostatic activity but were also bactericidal. For example, the Col-Dox-P system (at 8, 4, and 8 μg mL-1, respectively) and the Col-Rif-P system (at 4, 8, and 16 μg mL-1, respectively) were able to kill >99.999% of planktonic P. aeruginosa cells within 3 h of treatment. More importantly, an improvement of the therapeutic/selectivity index was achieved via combination therapy. Taking the Col-Dox-P system as an example, its biocompatibility with murine embryonic fibroblast cells was found to be comparable to that of polymer P alone despite the synergistic enhancement in antimicrobial activity of the combination. This resulted in a significant increase in selectivity by 16-fold for the Col-Dox-P combination system compared to P alone. Furthermore, the broad applicability of this tri-system strategy was demonstrated via the successful application of the AMP melittin in place of Col or P. Overall, this study sheds new insights on the application of membrane-disrupting antimicrobial agents in combination therapy and their potential for safer clinical use. Additionally, the information gathered in this study could inform the development of future combination therapy systems involving the simultaneous employment of multiple AMPs with antibiotics.

Introduction There has been renewed interest in the therapeutic use of bacteriophages (phages); however, standardised therapeutic protocols are lacking, and there is a paucity of rigorous clinical trial data assessing efficacy.Methods and analysis We propose an open-label, single-arm trial investigating a standardised treatment and monitoring protocol for phage therapy. Patients included will have exhausted other therapeutic options for control of their infection and phage therapy will be administered under Australia’s Therapeutic Goods Administration Special Access Scheme. A phage product with high in vitro activity against the targeted pathogen(s) must be available in line with relevant regulatory requirements. We aim to recruit 50–100 patients over 5 years, from any public or private hospitals in Australia. The standardised protocol will specify clinical assessments and biological sampling at scheduled time points. The primary outcome is safety at day 29, assessed by the frequency of adverse events, and overseen by an independent Data Safety Monitoring Board. Secondary outcomes include long-term safety (frequency of adverse events until at least 6 months following phage therapy), and feasibility, measured as the proportion of participants with>80% of minimum data available for analysis. Additional endpoints assessed include clinical response, patient/guardian reported quality of life measures, phage pharmacokinetics, human host immune responses and microbiome analysis. All trial outcomes will be summarised and presented using standard descriptive statistics.Ethics and dissemination Participant inclusion will be dependent on obtaining written informed consent from the patient or guardian. The trial protocol was approved by the Sydney Children’s Hospitals Network Human Research Ethics Committee in December 2021 (Reference 2021/ETH11861). In addition to publication in a peer-reviewed scientific journal, a lay summary of study outcomes will be made available for participants and the public on the Phage Australia website (https://www.phageaustralia.org/).Trial registration number Registered on ANZCTR, 10 November 2021 (ACTRN12621001526864; WHO Universal Trial Number: U1111-1269-6000).

Phage Directory has recently partnered with Phage Australia to help optimize Australia's data-centric standardized approach to personalized phage therapy. Here is a behind-the-scenes look at the genesis of Phage Australia, how the Phage Directory-Phage Australia partnership started, and what it is working toward.

Traditional studies using cancer cell lines are often performed on a two-dimensional (2D) cell culture model with a low success rate of translating to Phase I or Phase II clinical studies. In comparison, with the advent of developments three-dimensional (3D) cell culture has been championed as the latest cellular model system that better mimics in vivo conditions and pathological conditions such as cancer. In comparison to biospecimens taken from in vivo tissue, the details of gene expression of 3D culture models are largely undefined, especially in mesothelioma – an aggressive cancer with very limited effective treatment options. In this study, we examined the veracity of the 3D mesothelioma cell culture model to study cell-to-cell interaction, gene expression and drug response from 3D cell culture, and compared them to 2D cell and tumor samples. We confirmed via SEM analysis that 3D cells grown using the spheroid methods expressed highly interconnected cell-to-cell junctions. The 3D spheroids were revealed to be an improved mini-tumor model as indicated by the TEM visualization of cell junctions and microvilli, features not seen in the 2D models. Growing 3D cell models using decellularized lung scaffold provided a platform for cell growth and infiltration for all cell types including primary cell lines. The most time-effective method was growing cells in spheroids using low-adhesive U-bottom plates. However, not every cell type grew into a 3D model using the the other methods of hanging drop or poly-HEMA. Cells grown in 3D showed more resistance to chemotherapeutic drugs, exhibiting reduced apoptosis. 3D cells stained with H&E showed cell-to-cell interactions and internal architecture that better represent that of in vivo patient tumors when compared to 2D cells. IHC staining revealed increased protein expression in 3D spheroids compared to 2D culture. Lastly, cells grown in 3D showed very different microRNA expression when compared to that of 2D counterparts. In conclusion, 3D cell models, regardless of which method is used. Showed a more realistic tumor microenvironment for architecture, gene expression and drug response, when compared to 2D cell models, and thus are superior preclinical cancer models.

Adjunctive phage therapy was used in an attempt to avoid catastrophic outcomes from extensive chronic Pseudomonas aeruginosa osteoarticular infection in a 7-year-old child. Monitoring of phage and bacterial kinetics allowed real-time phage dose adjustment, and along with markers of the human host response, indicated a significant therapeutic effect within two weeks of starting adjunctive phage therapy. These findings strongly suggested the release of bacterial cells or cell fragments into the bloodstream from deep bony infection sites early in treatment. This was associated with transient fever and local pain and with evidence of marked upregulation of innate immunity genes in the host transcriptome. Adaptive immune responses appeared to develop after a week of therapy and some immunomodulatory elements were also observed to be upregulated.

The mechanisms underpinning beta-cell compensation for obesity-associated insulin resistance and beta-cell failure in type 2 diabetes remain poorly understood. We used a large-scale strategy to determine the time-dependent transcriptomic changes in islets of diabetes-prone db/db and diabetes-resistant ob/ob mice at 6 and 16 weeks of age. Differentially expressed genes were subjected to cluster, gene ontology, pathway and gene set enrichment analyses. A distinctive gene expression pattern was observed in 16 week db/db islets in comparison to the other groups with alterations in transcriptional regulators of islet cell identity, upregulation of glucose/lipid metabolism, and various stress response genes, and downregulation of specific amino acid transport and metabolism genes. In contrast, ob/ob islets displayed a coordinated downregulation of metabolic and stress response genes at 6 weeks of age, suggestive of a preemptive reconfiguration in these islets to lower the threshold of metabolic activation in response to increased insulin demand thereby preserving beta-cell function and preventing cellular stress. In addition, amino acid transport and metabolism genes were upregulated in ob/ob islets, suggesting an important role of glutamate metabolism in beta-cell compensation. Gene set enrichment analysis of differentially expressed genes identified the enrichment of binding motifs for transcription factors, FOXO4, NFATC1, and MAZ. siRNA-mediated knockdown of these genes in MIN6 cells altered cell death, insulin secretion, and stress gene expression. In conclusion, these data revealed novel gene regulatory networks involved in beta-cell compensation and failure. Preemptive metabolic reconfiguration in diabetes-resistant islets may dampen metabolic activation and cellular stress during obesity.

After a century of use in human infection, the preparation and administration of therapeutic bacteriophages (phages) still relies on ad hoc partnerships of researchers, biotech companies, clinicians and regulators. There is a clear need to improve the reproducibility, safety and speed of the provision of suitable phages. Here we discuss the specific characteristics and challenges of a sustainable phage biobank and, as we build a national consortium aimed at delivering phage therapeutics, suggest a roadmap toward national biobanking and phage therapy initiatives using the Australian context as a model.

Approximately 10% of global health research is devoted to 90% of global disease burden (the so-called “10/90 Gap”) and it often neglects those diseases most prevalent in low-income countries. Antibiotic resistant bacterial infections are known to impact on healthcare, food security, and socio-economic fabric in the developing countries. With a global antibiotic resistance crisis currently reaching a critical level, the unmet needs in the developing countries are even more striking. The failure of traditional antimicrobials has led to renewed interest in century-old bacteriophage (phage) therapy in response to the urgent need to develop alternative therapies to treat infections. Phage therapy may have particular value in developing countries where relevant phages can be sourced and processed locally and efficiently, breaking specifically the economic barrier of access to expensive medicine. Hence this makes phage therapy an attractive and feasible option. In this review, we draw our respective clinical experience as well as phage therapy research and clinical trial, and discuss the ways in which phage therapy might reduce the burden of some of the most important bacterial infections in developing countries.

OBJECTIVE:Aging and chronic glucocorticoid excess share a number of critical features, including the development of central obesity, insulin resistance and osteoporosis. Previous studies have shown that skeletal glucocorticoid signalling increases with aging and that osteoblasts mediate the detrimental skeletal and metabolic effects of chronic glucocorticoid excess. Here, we investigated whether endogenous glucocorticoid action in the skeleton contributes to metabolic dysfunction during normal aging.METHODS:Mice lacking glucocorticoid signalling in osteoblasts and osteocytes (HSD2OB/OCY-tg mice) and their wild-type littermates were studied until 3, 6, 12 and 18 months of age. Body composition, adipose tissue morphology, skeletal gene expression and glucose/insulin tolerance were assessed at each timepoint. Leptin sensitivity was assessed by arcuate nucleus STAT3 phosphorylation and inhibition of feeding following leptin administration. Tissue-specific glucose uptake and adipose tissue oxygen consumption rate were also measured.RESULTS:As they aged, wild-type mice became obese and insulin-resistant. In contrast, HSD2OB/OCY-tg mice remained lean and insulin-sensitive during aging. Obesity in wild-type mice was due to leptin resistance, evidenced by an impaired ability of exogenous leptin to suppress food intake and phosphorylate hypothalamic STAT3, from 6 months of age onwards. In contrast, HSD2OB/OCY-tg mice remained leptin-sensitive throughout the study. Compared to HSD2OB/OCY-tg mice, leptin-resistant wild-type mice displayed attenuated sympathetic outflow, with reduced tyrosine hydroxylase expression in both the hypothalamus and thermogenic adipose tissues. Adipose tissue oxygen consumption rate declined progressively in aging wild-type mice but was maintained in HSD2OB/OCY-tg mice. At 18 months of age, adipose tissue glucose uptake was increased 3.7-fold in HSD2OB/OCY-tg mice, compared to wild-type mice.CONCLUSIONS:Skeletal glucocorticoid signalling is critical for the development of leptin resistance, obesity and insulin resistance during aging. These findings underscore the skeleton's importance in the regulation of body weight and implicate osteoblastic/osteocytic glucocorticoid signalling in the aetiology of aging-related obesity and metabolic disease.

Introduction: Bacteriophage therapy is emerging as an approach to highly resistant and severe infection. Randomised studies are lacking but there have been some high-profile examples of successful salvage therapy using phages for highly antibiotic-resistant infection in critically ill patients. Here we describe the likely place of these agents in the pharmacopoiea and outline our world-first experience of treating fifteen critically ill patients with adjunctive GMP-quality bacteriophage cocktail, including for endocarditis and septic shock. Objectives/Aims: The aim of our study was to assess safety and tolerability of adjunctive bacteriophage therapy in patients with severe Staphylococcus aureus and Pseudomonas aeruginosa infections, with particular attention to practical aspects of bacteriophage delivery in the intensive care unit (ICU) including compatibility, toxicity and safety for patients and staff. Methods: In conjunction with the patient’s prescribed antibiotics regime, 14 consented patients with S. aureus sepsis, including infective endocarditis (n=8) were treated for 14 days with AB-SA01 (AmpliPhi Biosciences) based on a locally-approved protocol (registered under Therapeutic Goods Administration and Clinical Trial Notification). There was also one case of nebulised and intravenous antipseudomonal therapy. Physiological, haematological and biochemical markers, and mortality at day 28 and day 90 were measured. Results: Seven of thirteen (54%) patients survived past day 28, six of seven patients (86%) survived past day 90 and one patient was not susceptible to AB-SA01 and was excluded from iTT analysis. During therapy, we observed reduction in inflammatory markers, no adverse events and no evidence of phages were found on environmental swabs. We used correct personal protective equipment including P2/N95 fluid resistant masks during nebulisation of phages. Conclusion: We demonstrated for the first time that phage therapy produced under GMP conditions is safe and well-tolerated in critically ill patients. Our practical experience highlighted it is safe for healthcare professionals to administer this therapy.