Researcher: Maria Stroyakovski, Biochemistry
Mentor: Iona Cuthbertson, University of Cambridge
Antimicrobial resistance (AMR) is considered to be the silent pandemic, which is estimated to be responsible for 10 million deaths annually by the year 2050. However, findings published in The Lancet by Antimicrobial Resistance Collaborators (2022) show that already in 2019 over a million deaths worldwide could be directly attributed to AMR. To place this into context, that is just under the value for global HIV and malaria deaths combined.
Of those pathogens thar are implicated, only one – Streptococcus pneumoniae – is preventable through vaccination. Therefore, this is an issue that predominantly affects those of lower income, as they have restricted access to more expensive second line antibiotic treatment.
Bacteriophages are natural microscopic predators of bacteria and they have been killing bacterial hosts for billions of years. As antimicrobial agents, they are specific, abundant, and ubiquitous, meaning that they do not harm human or healthy bacterial cells, and can be administered at low cost. They can also be used in combination with antibiotics that are already in use, prolonging their efficacy. Clinical trials using bacteriophage therapy are already taking place in the US, France, Switzerland, Belgium, the UK, and Australia, however their efficacy in compassionate use cases has already been demonstrated (Little et al., 2022; Aslam et al., 2020; Dedrick et al., 2019; Chan et al., 2018; LaVergne et al., 2018; Abedon et al., 2011).
The current system for sourcing viable phages for compassionate use is wildly ineffective. The researcher plans to create a centralised Phage Biobank that can rapidly and accurately provide necessary phages for treatment. The uniqueness of the approach is focusing on acquiring and standardising phages already in existence, as opposed to isolating them de novo. The plan is to create a repository for phages that researchers would be motivated to use, as it would provide services such as phage purification and high titre lysate preparation, storage, propagation, and eventually sequencing. These phages would then be characterised in a standardised manner, allowing for use in medical treatments, as well as facilitating collaboration between different phage labs around the world.
In the long-term, by increasing the number of successful compassionate use phage therapy cases, we can begin to build a well-supported argument for approval of bacteriophage use in a medical setting, therefore overcoming some of the problems associated with clinical trials for personalised medicine.
The first step will be establishing a Phage Biobank in the UK. However the overarching goal is to make this an accessible therapy for AMR infections in countries where specialised antibiotics are not available. The question for the i-Team is therefore to investigate how attractive this proposal would be to clinicians in low and middle income countries. Are there sufficient research centres working on phages to create a self-sufficient system, or would it have to be a multi-national collaboration? What might be the regulatory issues around receiving live bacteriophage viruses from abroad when there is no clinical trial data backing their efficacy?
References:
Abedon, S. T., Kuhl, S. J., Blasdel, B. G., & Kutter, E. M. (2011). Phage treatment of human infections. Bacteriophage, 1(2), 66. https://doi.org/10.4161/BACT.1.2.15845
Aslam, S., Lampley, E., Wooten, D., Karris, M., Benson, C., Strathdee, S., & Schooley, R. T. (2020). Lessons Learned From the First 10 Consecutive Cases of Intravenous Bacteriophage Therapy to Treat Multidrug-Resistant Bacterial Infections at a Single Center in the United States. Open Forum Infectious Diseases, 7(9). https://doi.org/10.1093/OFID/OFAA389
Chan, B. K., Turner, P. E., Kim, S., Mojibian, H. R., Elefteriades, J. A., & Narayan, D. (2018). Phage treatment of an aortic graft infected with Pseudomonas aeruginosa. Evolution, Medicine, and Public Health, 2018(1), 60–66. https://doi.org/10.1093/EMPH/EOY005
Dedrick, R. M., Guerrero-Bustamante, C. A., Garlena, R. A., Russell, D. A., Ford, K., Harris, K., Gilmour, K. C., Soothill, J., Jacobs-Sera, D., Schooley, R. T., Hatfull, G. F., & Spencer, H. (2019). Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus. Nature Medicine 2019 25:5, 25(5), 730–733. https://doi.org/10.1038/s41591-019-0437-z
LaVergne, S., Hamilton, T., Biswas, B., Kumaraswamy, M., Schooley, R. T., & Wooten, D. (2018). Phage Therapy for a Multidrug-Resistant Acinetobacter baumannii Craniectomy Site Infection. Open Forum Infectious Diseases, 5(4). https://doi.org/10.1093/OFID/OFY064
Little, J. S., Dedrick, R. M., Freeman, K. G., Cristinziano, M., Smith, B. E., Benson, C. A., Jhaveri, T. A., Baden, L. R., Solomon, D. A., & Hatfull, G. F. (2022). Bacteriophage treatment of disseminated cutaneous Mycobacterium chelonae infection. Nature Communications 2022 13:1, 13(1), 1–7. https://doi.org/10.1038/s41467-022-29689-4
Murray, C. J., Ikuta, K. S., Sharara, F., Swetschinski, L., Robles Aguilar, G., Gray, A., Han, C., Bisignano, C., Rao, P., Wool, E., Johnson, S. C., Browne, A. J., Chipeta, M. G., Fell, F., Hackett, S., Haines-Woodhouse, G., Kashef Hamadani, B. H., Kumaran, E. A. P., McManigal, B., … Naghavi, M. (2022). Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. The Lancet, 399(10325), 629–655. https://doi.org/10.1016/S0140-6736(21)02724-0