Phage therapy for difficult-to-treat infections in children, with Dr. Ameneh Khatami
Issue 143 |
September 10, 2021
9 min read
In our July PHAVES series, Dr. Ameneh Khatami, a paediatric infectious disease physician and senior lecturer at the University of Sydney, spoke about phage therapy for difficult to treat infections in children. Here’s the recording, along with a recap by Sayde Perry & Stephanie Lynch!
Submit your next paper to PHAGE journal’s upcoming Phage Informatics and AI special issue! They’re looking to publish novel phage bioinformatics tools, AI in phage biology and therapy, and tools for host discovery and prediction, phage characterization, database tools, and more!
Jennifer Mahony (University College Cork, Ireland) published a commentary in mSystems on the use of cell surface polysaccharides as a common strategy for phage adsorption. She discussed how identification of common host recognition and binding strategies facilitates development of rational starter culture systems, and the implications for sustainable food production systems.
Cell surface proteinPhage adsorption
Xin You (Helmholtz Centre for Environmental Research, Germany) and colleagues published a preprint on phage co-transport with hyphal-riding bacteria. They report the ability of hyphal-riding bacteria to transport lytic phages and utilize them as ‘weapons’ during colonization of new water-unsaturated habitats. Their data emphasize the importance of this phenomenon in regulating fitness and composition of microbial populations.
FitnessLytic phages
Olivia Williams Barber (Northwestern University, USA) and colleagues published a minireview in mSystems on how the future of phage therapy will promote antimicrobial susceptibility. They examined bacterial resistance mechanisms, the current state of phage therapy, how phage therapy can augment strategies to combat resistance, and the role of efflux pumps in antimicrobial resistance.
The Moniruzzaman lab at the University of Miami, Florida is recruiting 1-2 PhD students for Fall 2022 to study giant virus ecology and evolution through experimental and bioinformatic approaches. Please send an email detailing your interest and CV to: [email protected].
PhD projectResearch AssistantStructural Biology
The Taylor Group at the University of Copenhagen, Denmark is hiring a Research Assistant for 4 months, to then continue as a PhD fellow for 3 years. This position will use cryo-electron microscopy combined with functional techniques to study the mechanisms of transport across biological membranes, including phages.
The Silveira Lab at the University of Miami, Florida is hiring a Postdoctoral Associate to study the tripartite relationships between phage-bacteria interactions in coral reef.
FacultySynthetic phages
The Mayo Clinic is seeking candidates for a faculty position to develop, study and test gene therapy approaches for clinical indications and translate those findings into human testing. Examples of research areas include: Gene replacement using CRISPR, Viral delivery of transgenes, or creation of synthetic phages to target and kill drug resistant pathogens.
Anyone can post a message to the phage community — and it could be anything from collaboration requests, post-doc searches, sequencing help — just ask!
For PHAVES #22 next week, Dr. Saima Aslam, MD (IPATH, UCSD, California) will present ‘Clinical phage therapy: Learning from patients’ on Sept 20 at 9AM Pacific! Hear about her experience in treating patients with phage and ask her all your questions! Register here!
Stephanie Lynch will host the next Phage Phun session, which will be Wednesday September 29 at 3PM Pacific (an Australian friendly time!). Join us for this informal virtual networking session by registering here. (If you’re already signed up for the PHAVES series or a past Phage Phun, no need to register again; we’ll send you the link closer to the date).
FunPhage phun!Virtual Event
Phage therapy for difficult-to-treat infections in children, with Dr. Ameneh Khatami
I am a fourth-year undergraduate student at Pomona College where I study molecular biology. I currently research bacteriophage interactions with Vibrio cholerae! After graduating, I hope to continue learning about phage biology, bacterial infections, and phage therapy through a research exchange or a PhD program. I love meeting people in the phage community and would eagerly welcome any opportunities to chat!
Stephanie is a postdoctoral researcher for the Iredell Group at Westmead Institute for Medical Research, NSW. Her project focuses on phage therapy for compassionate human cases (as part of Phage Australia), with a particular interest in Staphylococcal phages. In 2021, Stephanie completed her thesis titled ‘Exploring phage therapy for Staphylococcus pseudintermedius infections in canines’. Steph is always willing to chat about phage research and would like to connect with phage biotech companies.
Standardized protocols for dosing and clinical monitoring do not exist yet.
It can be hard to monitor the clinical efficacy of treatment.
There is limited supply of readily available phage that match specific bacterial isolates and the development of such a phage supply can be lengthy.
Existing regulations for phage use are outdated especially for phages considered to be synthetic or genetically modified.
Medical community has limited awareness about phage therapy.
Advantages:
Phages have low toxicity and have minimal impacts on patients’ microbiomes.
Phages can be used to treat bacteria that are resistant to antibiotics and therefore reduce the selection for AMR.
Unlike other treatment components, phages can penetrate bacterial biofilms very well.
Despite these challenges, phage therapy is being used in compassionate cases where all other treatment options have been exhausted. Within this seminar, Dr. Khatami spoke about two cases where phage therapy was used in children.
Case 1
The patient case
A 7-year old girl was involved involved in a motor vehicle accident that required prolonged hospital stays and multiple surgeries, including an in situ hardware placement. Following surgical intervention, the patient reported chronic heel pain and the presence of discharge from the bottom of her heel. Bacterial cultures from the discharge revealed isolates of Pseudomonas aeruginosa which harboured the blaNDM-1 gene, meaning isolates were resistant to most antibiotics available. Due to this high resistance profile, only colistin and aztreonam were left, leaving a high chance of ‘non-cure’, therefore, phages were trialed.
Phage therapy course of treatment
Following a phage request through Phage Directory, a GMP-grade phage product was supplied from Adaptive Phage Therapeutics.
Synergy test of the phage with colistin and aztreonam showed no synergistic effects but also no antagonist effects, therefore, dual therapy was used.
Through monitoring the phage kinetics, the patient’s immune response, and the patient symptoms, results showed:
The patient had a fever, increased heel pain and increased inflammatory markers following the first dose of phage. However, only low grade fevers following the second and third dose. Beyond these initial doses, there were no fevers reported with subsequent doses.
Transcriptomic analysis revealed that on Day 2 following phage administration, the patient had a strong upregulation of genes involved in the innate immune response. However, by Day 29 (2 weeks after phage therapy), the transcriptome of the patient was similar to baseline.
2 weeks following phage therapy, the patient reported a reduction in heel pain and an improvement to mobilization.
Conclusions
While the success of this case was very exciting, as it demonstrated that phage therapy was feasible, practical and safe, it is unknown how much of the success was a result of the antibiotics or the phage.
The case involved a 12-year old diagnosed with cystic fibrosis who was suffering from clinical symptoms such as pancreatic insufficiency, sinus disease, and nasal polyps. Microbiological analysis resulted in mixed bacterial cultures, with Mycobacterium abscessus showing persistent colonisation over years, and the isolates showed high antibiotic-resistance. The patient received 3 months of antibiotics with an 18 month maintenance period, however, the patient’s chest CT and lung function were declining, therefore, phage therapy was considered.
Phage therapy course of treatment
Upon request, Professor Graham Hatfull at the University of Pittsburgh identified and supplied two mycobacteriophages against the M. abscessus.
The compassionate use of phage therapy was approved through regulatory bodies, however, as one of the phages was considered a GMO, there were stricter containment regulations.
The two phages were delivered through intrabronchial administration for 21 days, and additionally through intravenous administration for 10 months, which ceased 2 months ahead of schedule due to clinical success.
Antibiotics were also used for dual therapy alongside the phage administration.
Conclusions
For the first time in 4 years, the patient’s bacterial cultures were negative for M. abscessus following phage and antibiotic dual therapy.
Future directions
Results such as these highlight that phage therapy is safe for use in children, however, clinical trials need to be run in adults and children simultaneously, with a focus on ‘individualised’ treatment for each patient, which isn’t generally considered in standard clinical trials. Additionally, there is a need to streamline the use of phages in patients, from characterisation and sequencing, to GMP-grade manufacturing and improved therapeutic monitoring protocols.
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Many thanks to Atif Khan and Stephanie Lynch for finding, summarizing and editing this week’s phage news, jobs and community posts!
