Invited Speaker Australian Society for Microbiology Annual Scientific Meeting 2021

BIOLOGY OF PHAGE THERAPY: TARGETING MULTIDRUG RESISTANT INFECTIONS (#96)

Aleksandra Petrovic Fabijan 1 , Ameneh Khatami 1 2 , Alicia Fajardo-Lubian 1 3 , Ruby Lin 1 3 , Carola Venturini 1 3 , Muhammad Kamruzzaman 1 , Jon R Iredell 1 3 4
  1. University of Sydney , Sydney, NSW, Australia
  2. The Children's Hospital at Westmead, Westmead, NSW, Australia
  3. University of Sydney , Westmead, NSW, Australia
  4. Centre for Infectious Diseases and Microbiology , The Westmead Hospital, Westmead, NSW, Australia

Phage therapy is increasingly proposed when antibiotics fail and thus has great promise as a solution for antimicrobial resistance in bacteria. Our team was first-in-the-world to trial: (1) IV use of GMP phage for severe Staphylococcus aureus sepsis1 (n=14), (2) IV and nebulised phage for Pseudomonas aeruginosa pneumonia2 (n=1) and (3) IV phage for extensive P. aeruginosa osteoarticular infection in child (n=1)3. Data from these studies provided an important insight into dosing regimens, kinetics and treatment response and importantly phage-bacteria co-evolution in vivo. Our team is one of few in world to use genetically modified phage therapy to treat MDR-Mycobacterium abscessus lung infection in paediatric patients with cystic fibrosis4. Our lab is a recognised leader in this area and has led the development of the Australian Phage Network, with international connections to large phage libraries, thus making these available to Australian patients5. Our work directly aims at the most important pathogens globally: (1) Shigella, a leading cause of death in children worldwide; (2) carbapenem-resistant Klebsiella and Escherichia coli; (3) P. aeruginosa and M. abscessus, both driving terrible morbidity and mortality in children with cystic fibrosis. In addition, we have developed and routinely use the needed companion diagnostics and expect to develop phage therapy as an NSW-led national initiative. Our basic research focuses on understanding the phage therapy efficacy under suboptimal conditions expected to be find in vivo and we have developed the methods to test this in clinically relevant bacterial forms (e.g. L-forms). Our preliminary data suggest that the phages most common in nature and in therapy (T4-like) are ineffective against such forms, but that others (e.g. V5-like) remain fully functional. We envisage to develop robust strategies and pipelines and optimal phage therapies to prevent therapeutic failure and development of resistance and enable safe and efficient use of phages in the clinic6.

 

We thank Jeff Errington and Katarzyna Mickiewicz from Newcastle University (UK) for their contributions to the L-form work.

  1. Petrovic Fabijan A, Lin R, Ho J, Maddocks S and Iredell J. Safety of bacteriophage therapy in severe Staphylococcus aureus infection. Nat Microbiol 5, 465–472 (2020). https://doi.org/10.1038/s41564-019-0634-z.
  2. Maddocks S, Petrovic Fabijan A, Ho J, Lin RCY, Ben Zakour NL, Dugan C, Kliman I, Branston S, Morales S, Iredell JR. Bacteriophage Therapy of Ventilator-associated Pneumonia and Empyema Caused by Pseudomonas aeruginosa. Am J Respir Crit Care Med 200(9):1179-1181 (2019). doi: 10.1164/rccm.201904-0839LE.
  3. Khatami A, Lin R, Petrovic-Fabijan A, et al. Therapeutic monitoring of the host-bacterium-phage interaction in a child. Research Square (2020) doi: 10.21203/rs.3.rs-110673/v1.
  4. Dedrick RM, Guerrero-Bustamante CA, Garlena RA, Russell DA, Ford K, Harris K, Gilmour KC, Soothill J, Jacobs-Sera D, Schooley RT, Hatfull GF, Spencer H. Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus. Nat Med 25(5):730-733 (2019). doi: 10.1038/s41591-019-0437-z.
  5. Lin R, Sacher JC, Ceyssens PJ, Zheng J, Khalid A, Iredell JR; Australian Phage Biobanking Network. Phage Biobank: Present Challenges and Future Perspectives. Curr Opin Biotechnol 68:221-230 (2021). doi: 10.1016/j.copbio.2020.12.018.
  6. Petrovic Fabijan A, Khalid A, Maddocks S, Ho J, Gilbey T, Sandaradura I, Lin RC, Ben Zakour N, Venturini C, Bowring B, Iredell JR. Phage therapy for severe bacterial infections: a narrative review. Med J Aust 212(6):279-285 (2019). doi: 10.5694/mja2.50355.