Collaboration leads to phage therapy success

Issue 22 | March 21, 2019
8 min read

The first case of phage therapy in Israel shows how patients can benefit from collaborations between academia, medicine, military and biotech.

This week, we’re going over a collaborative effort that led to using phages to treat a patient facing leg amputation. This was just published as a case report.

The collaboration involved:

What’s New

The 4th International Hands-on Phage Biotechnology Course takes place June 17-21, 2019 in Braga, Portugal. Learn theory and techniques for studying phage-host interaction and performing phage genetic manipulation. Registration is now open! Prices go up April 1.

WorkshopPhage Techniques

This summer, a new phage journal, PHAGE: Therapy, Applications, and Research, will be launched by the publisher Mary Ann Liebert, Inc., and the editor in chief will be Dr. Martha Clokie!

New JournalPhage ApplicationsPhage Research

More phage defense systems?? (And a great article title!) Check out this new paper on Gordonia phages by Matthew T. Montgomery and colleagues in the Hatfull lab.

Viral defenseProphage defenseGordonia terrae

Cherry canker is a devastating tree disease that could one day be treated by phages. Learn about the work George Sundin’s lab at Michigan State University is doing to make this a reality!

Phage BiocontrolPhages in agriculture

If you want to better understand the funds available for AMR drug development, here’s a slideshow from a talk given this week by John Rex of the Wellcome Trust. It explains what’s available, the different funding models that exist, provides lots of links, discusses pitfalls, and lists a lot of upcoming meetings where you can learn more.

AMR Drug DevelopmentFunding Opportunities

Latest Jobs

PhD student position: Role of phages in the gut microbiome

University of Warwick, Quadram Institute,
Warwick, UK

Dr. Eleanor Jameson, Prof. Orkun Soyer, Prof. Arjan Narbad

The gut microbiome consists of viruses, bacteria, archaea and eukaryotes. To date research efforts have focused on bacteria, however the gut virome remains underexplored, even though the viral (bacteriophages) interactions are intrinsically linked to the dynamics of the gut microbiome. The project will seek to understand overall changes to the gut microbiome with increased phage loads.

PhD MicrobiomeGutPhage

PhD student position: Role of phages in the gut microbiome

Midlands Integrative Biosciences Training Partnership,
Warwick, UK

Dr. Eleanor Jameson

The project will seek to understand overall changes to the gut microbiome with increased phage loads. This will involve analysis of the bacteria, archaea, eukaryotes and viruses and their metabolites in response to phage treatments in gut microbiome microcosms.

PhD MicrobiomeGut

Postdoctoral position: Bioinformatics / Microbial genome evolution

“IBG-1, Forschungszentrum Jülich”,
Jülich, Germany

Dr. Julia Frunzke

The Institute of Bio- and Geosciences (IBG-1) of the Forschungszentrum Jülich performs research in the field of molecular and applied microbiology. The successful candidate will work on an ERC funded project and will be part a Helmholtz research group located at the IBG-1. Current projects of the group focus on phage-host regulatory interaction and the integration of prophage elements in host networks. Applications from experimentalists wanting to switch to data analysis are welcome.

Post Doc BioinformaticsGenomicsProphage

Community Board

Anyone can post a message to the phage community — and it could be anything from collaboration requests, post-doc searches, sequencing help — just ask!

The community board is empty this week. Be the first to post something for next week!

Collaboration leads to phage therapy success

Profile Image
Phage microbiologist and co-founder of Phage Directory
Co-founder
Phage Directory, Atlanta, GA, United States

Jessica Sacher is a co-founder of Phage Directory and has a Ph.D in Microbiology and Biotechnology from the University of Alberta.

For Phage Directory, she takes care of the science, writing, communications, and business aspects.

This week, we’re going over a recently-published phage therapy case report.

What was the patient dealing with?

A patient in Israel (a 42 year old male who’d been in a motor vehicle accident) sustained open fractures in his legs, and contracted an antibiotic-resistant, poly-microbial bone infection.

His leg was colonized with both extensively antibiotic-resistant Acinetobacter baumannii and multi-drug resistant Klebsiella pneumoniae.

Normally, this would necessitate amputation of the leg. However, the patient refused.

What was done?

After seven months of in-hospital treatment with surgeries and antibiotics, personalized phage therapy was combined with antibiotics to treat the wounds.

What’s personalized phage therapy again?

Personalized phage therapy involves selecting one or more phages for treatment based on their demonstrated ability to kill the patient’s exact strain of bacteria.

What was the outcome?

The patient’s infection was cleared, his wounds healed, and his leg did not have to be amputated.

The nitty gritty: How was this done?

Identifying the bacteria

The medical team at the Hadassah Hebrew University Medical Center cultured the bacteria from the patient’s leg wound, identified the bacteria (A. baumannii and K. pneumoniae), and tested them for antibiotic susceptibility.

Choosing and preparing the phages

  • Adaptive Phage Therapeutics (APT) tested the patient’s bacteria for phage susceptibility against the US Navy’s large library of phages.
  • One anti-Acinetobacter phage and one anti-Klebsiella phage was selected based on their ability to effectively kill the patient’s isolates.
  • The phages were propagated and clinical-grade phages were produced for the patient.

Tracking phage resistance

Ronen Hazan’s lab at the Hebrew University of Jerusalem tracked emergence of phage-resistant mutants over time by culturing phage and bacteria together.

How were the phages administered?

  • The two phages were given intravenously (IV) in combination with the antibiotics meropenem and colistin.
  • Dose: 1 mL of around 10^7 PFU/mL each, three times a day for 5 days.
  • Endotoxin levels: between 5 and 35 EU/mL

How did the patient respond to phage therapy?

  • For the first day, phage therapy was done in the intensive care unit in case of adverse reactions, but none were observed.
  • After the first course of treatment, A. baumannii was still isolated from the leg wound, so a second course was administered.
  • After a few days, the wound began to heal and the patient’s pain diminished. The patient was discharged.

What was observed long-term?

  • Over the next eight months, no more positive A. baumannii and K. pneumoniae cultures were obtained from the patient. The wounds closed, and the pain disappeared.
  • Methicillin-sensitive Staphylococcus aureus was isolated in the leg three months after phage therapy, but it was successfully cleared with antibiotics.

Where did the phages end up?

No active phages were found in the patient’s blood, urine, stool or saliva.

Was phage resistance an issue?

Phage resistant A. baumannii cells grew in the lab. However, within a few weeks, Dr. Hazan’s team isolated a new phage (from sewage) that could kill the phage-resistant mutant. Comparison of the genomes of the phage-resistant mutant and the parent strain showed differences in 37 genes!

Fortunately, although phage resistance was seen in the lab, it was never observed in the patient, so the new phage didn’t need to be used.

Interesting note: combinations matter

The patient’s Klebsiella isolate wasn’t resistant to meropenem unless it was co-cultured alongside the (meropenem-resistant) Acinetobacter isolate.

When grown together, the two bacteria could only be inhibited by the antibiotics if the phages were also present.

What was the process of getting approval to try phage therapy?

The teams involved got their experimental treatment protocol and informed consent agreement approved by both the hospital’s ethics committee and the Israeli Ministry of Health. The patient then gave his informed consent, and the treatment was administered.

Conclusions

This was clearly a success story for the patient. As well, this case brings us several useful insights about personalized phage therapy:

  • It can be effective in clearing a poly-microbial limb-threatening bone infection.
  • It can be done to combat two bacterial pathogens at once.
  • It can be adaptable in the face of phage resistance.

Of note, this was the first case of phage therapy in Israel.

Further reading

  • Learn how Adaptive Phage Therapeutics’ high-throughput phage susceptibility testing system works: APT website / Paper describing the technology.
  • Learn more about the phage therapy work Ronen Hazan’s lab is doing at the Hebrew University of Jerusalem. Also, check out his lab’s major focus on student mentorship—we love how he celebrates the work of his students!

Main source for this issue:

Nir-Paz, R., Gelman, D., Khouri, A., Sisson, B. M., Fackler, J., Alkalay-Oren, S., … Hazan, R. (2019). Successful treatment of antibiotic resistant poly-microbial bone infection with bacteriophages and antibiotics combination. Clinical Infectious Diseases. doi:10.1093/cid/ciz222

Capsid & Tail

Follow Capsid & Tail, the periodical that reports the latest news in phage therapy and the phage community.

We send Phage Alerts to the community when doctors require phages to treat their patient’s infections. If you need phages, please email us.

Supported by

Leona M. and Harry B. Helmsley Charitable Trust

Crossref Member Badge