At the end of 2023, the International Bacteriophage Research Consortium (IBRC) & Open Source Pharma Foundation (OSPF), in association with the Indian Society for Bacteriophage Research and Therapy (SBRT), organized a series of talks featuring clinicians from the United States, Australia, India, and Georgia who have experience in delivering Phage Therapy. These talks were held during World Antibiotic Awareness Week (WAAW 2023), which aims to raise awareness about the antibiotic resistance crisis and promote antibiotic stewardship. The talks aimed to provide insights into phage therapy’s latest developments, challenges, and successful case studies to deepen the understanding among clinicians, researchers, and regulatory bodies.
The series featured several notable speakers (click the links below to watch the recordings!).
Dr. Gina Suh, an Infectious Diseases specialist, treated the Mayo Clinic’s first phage therapy patients and is currently heading efforts to create the Mayo Clinic Phage Therapy Program and run phage clinical trials. She shared her experiences with Compassionate Use Cases, including treating prosthetic joint infections, left ventricular device infections, and hepatic abscesses.
Dr. Robert Chip Schooley, a Professor at the University of California, San Diego and co-director of IPATH, discussed Unsettled Issues in Phage Therapeutics, drawing on his experience as the first physician to treat a patient with intravenous bacteriophage therapy in the United States.
Prof. Jonathan Iredell, an Infectious Diseases Physician at Westmead Hospital, Sydney, coordinates nationwide clinical trials related to life-threatening infections. While discussing their end-to-end national program, ‘Phage Australia’, he emphasized the importance of therapeutic phage characterization with respect to their growth curve.
Dr. Gopal Nath, from Banaras Hindu University, pioneered Clinical Bacteriophage Therapy in India. He shared his discernments based on his experience of treating about 200 cases of chronic/diabetic wound infections, ventilator-associated pneumoniae, and cases of septicaemia.
Dr. Mzia Kutateladze, Director of the G. Eliava Institute of Bacteriophages, Microbiology, and Virology and President of the Eliava Foundation, a collection of commercial spin-offs in Georgia, discussed her vast experience in coordinating phage research in the institute. She shared details on the development of phage cocktail products for infections.
The talks sparked discussions on various topics, including specifics on phage purification, storage conditions and viability, dosing intervals, the cost of treatment, scalability, regulatory hurdles, and the overall merits of phage therapy. The participants, including research scholars, scientists, clinicians, professors, start-up owners, and journalists, raised questions and concerns about the efficacy, specificity, and host range of bacteriophages, routes of phage delivery, in vivo vs. in vitro discordance, adaptive human immune response, and regulatory issues.
The common questions and concerns that arose after the talks are categorized and are listed below.
Technical specifics on therapeutic phages
Where are phages sourced from? Are there standard operating protocols for phage preparations? How stable are phage preparations? Does encapsulation or carriers like liposomes make phages more stable? Soil/water samples from nearby farms, animals, wastewater, and sewage are common isolation spots. Essential considerations in phage therapy are universally accepted protocols for phage preparation and purification, both on a small scale and on an industrial scale. The principal criterion for choosing phages for therapy is based on their lytic potential. The shelf life of most phages (at 4 degrees Celsius) is about two years.
Monophage Vs Phage Cocktail preparations. Clinicians favoured broad host range fixed cocktails, especially for infections like UTIs. An intimate knowledge of the local microflora allows for the development of phage cocktails in advance.
Antibiotic-phage and phage-phage synergy: How do phages behave differently in a cocktail? Can the synergies be predicted in vitro? Are there practical guides for the in vivo amplification effects of phages? The importance of phage banks and informed decisions on sourcing phages from the established biobanks vs. preparing customized phages; the need for mobile phage libraries or to rely upon established centres for procuring phages.
Endolysins. Phage-encoded lytic enzymes as recombinant proteins hold promise as enzybiotics. Being proteins, endolysins don’t amplify; hence, the production and therapy cost was considered higher than that for phages. Also, their PK and PD would be different from phages.
The technical specifics related to phage therapy
Delivery routes and dosing in phage therapy. Phage administration was acknowledged to be complicated. Depending on the anatomy of the infection, the dose and route of administration must be carefully chosen. Initially, endotoxins in phage preparations disallowed clinicians from using routes other than oral/topical; however, the modes are now expanding. Are there alternative delivery methods, such as aerosolization or targeted nanoparticles, that could improve phage delivery to specific infection sites, especially in cases involving intracellular pathogens like Mycobacterium sp.? The need to develop a rational framework was considered necessary.
Dosing: Monitoring pre-clinical trials usually indicates 2-3 doses as sufficient in less severe cases. While some clinicians preferred higher titres (10^9-10^10pfu/ml) of phages in fewer dosages, the other speakers preferred lower (~10^5 pfu/ml) titres but more frequent dosages.
Patients’ response to the phage treatment
Immune response to Phage Therapy: The queries on immune response were among the highest. Although the speakers did not consider it a major impediment, the probability of neutralizing antibodies negatively impacting the therapy wasn’t ruled out, especially in chronic infections. They were of the opinion that this response is still to be understood entirely.
Phage resistance: In mono-phage therapy, resistance can develop quickly, but with multiple phages, resistance can be delayed or may not occur during the course.
The practice of monitoring parameters during treatments, especially in cases where the release of endotoxins is anticipated, assures the safety of the treatment. The Bates-Jensen wound assessment tool is one such tool, and the monitored parameters include temperature, blood pressure, and oxygen saturation.
Genetically engineered phages
Engineered/modified phage therapeutics: How can synthetic biology approaches be leveraged to engineer phages with enhanced therapeutic properties, such as increased host specificity, prevention of lysogeny or resistance to bacterial defenses? What ethical considerations are associated with genetically modifying phages for therapeutic purposes, and how can we ensure responsible and transparent research practices? What are the environmental implications of using phages for therapy, including releasing genetically modified or introducing non-native phages into ecosystems?
Clinical trials
Deliberations on clinical trials attributed under-dosing, loss of phage viability, inefficiency of pre-prepared cocktails, lack of personalized preparation, etc., to the unsuccessful trials. All the panelists emphasized developing and implementing carefully structured clinical trials to assess the safety and effectiveness of phage therapy across various infection types, including optimizing concurrent antibiotic therapy in combination with phage therapy. The factors that would require thorough consideration are study design, criteria for selecting participants, defined endpoints, and comprehensive follow-up evaluations to ensure the production of reliable clinical data. A less emphasis on pre-clinical studies as a pre-requisite for using phages in clinical trials and human medicine appears to be a welcome step.
Conclusion
Despite the challenges and limitations discussed, the guest clinicians in the series expressed profound optimism and confidence in phage therapy as a potential solution to the antibiotic resistance crisis. They also highlighted the importance of interdisciplinary research approaches and collaboration, which can address complex challenges and drive innovation in phage therapy. However, given the value therapeutic phages hold, Material Transfer Agreements (MTAs) and the procedural delays for sharing phages and their products were identified as some of the crucial constraints in fruitful collaborations. They emphasized the need for standardized protocols for phage preparation and purification, the development of phage banks, and carefully structured clinical trials to assess the safety and effectiveness of phage therapy.
To sum up, the queries such as “What is the cost of the treatment?”, “Why can’t phage therapy be given early in patients’ illness?” “Why does phage therapy fail in some and succeed in others?” “By when can phage treatment become commercially available?” conveyed growing interest, acceptance, and somewhat impatience among the participants.
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