A century on, can phage therapy deliver in the management of multi-drug resistant bacterial infection?

Methicillin resistant S.aureus

As with my recent post on dendritic cell vaccines [Dendritic cell vaccines: back to the future], a news item brought to mind another therapeutic concept that’s been around for decades (tens of decades, actually) without ever finding its sweet spot.

Bacteria, in common with more complicated organisms, are susceptible to virus infection. These viruses (bacteriophage or “phage”) either destroy the bacteria after infection and replication or incorporate their DNA into that of the bacterial host and hijack the replication machinery to continually pump out fresh phage. Phage are highly specific for their target bacteria, are self-replicating and quick to mutate to overcome resistance.

On paper, these properties make for a potentially useful therapy, allowing the targeting of disease-causing bacteria without collateral damage among normal (and useful) bacteria. Starting in the 1920s, phage therapy gained a clinical following, although largely confined to Georgia and the rest of the Soviet Union (the pioneering laboratory, now known as the Eliava Institute, is still in operation and offering phage treatments).  In the West, antibiotic discovery and development reduced phage therapy to a minor topic of academic interest.

Fast-forward to the 21^st century, where the management of multi-drug resistant (MDR) infection, often involving very frail patients, is now a regular challenge and is fostering renewed interest in phage therapy. Although no phage therapy has ever received regulatory approval, the US Food and Drug Administration have permitted use as a treatment of last resort on a case by case basis.

There have been notable successes, including cure of a MDR infection of the pancreas; an individual with cystic fibrosis and a MDR lung infection was not so fortunate, AmpliPhi, a US company specialising in phage therapy development has treated MDR infections in two patients scheduled for lung transplantation, both resulting in successful outcomes.

Major hurdles remain before phage therapy can be relied on as a reliable weapon against MDR infection. The exquisite specificity of phage is two-edged: phage capable of eliminating the exact strain of infecting bacteria must be identified prior to therapy. Bacterial susceptibility to phage can change as infection progresses, and a cocktail of phage offers a higher chance of eliminating infection. AmpliPhi combined 15 different phage to treat lung infection in one patient.  Growing sufficient quantities of phage and removing all traces of potentially harmful bacterial components to allow safe intravenous administration is another technical challenge.

Solutions to the “find a phage” problem are in development, from the online Phage Directory, which attempts to match patients with available phage strains, through to the use of DNA sequencing and artificial intelligence by AmpliPhi, Adaptive Phage Therapeutics and EpiBiome.

AmpliPhi has successfully developed processes for the manufacture of pharmaceutical grade phage products and is banking that its “pre-mixed” phage cocktails for the treatment of MDR Staphylococcus aureus and MDR Pseudomonas aeurginosa infections will prove to be a practical and immediate means of delivering phage therapy. Drawing on sobering experience gained in a European study that set out to evaluate phage therapy in burns patients, Belgium has developed a legal and regulatory framework to promote timely preparation of therapeutic phage by research laboratories.

Mainstream acceptance (and commercial success) lies someway in the future. Defined “pre-mixed” phage cocktails pose less of a regulatory challenge but their efficacy and optimal use in infection management remains to be defined. “Bespoke” phage therapy has interesting parallels with personalized cancer therapies, such as CAR-T and neoantigen vaccines, where therapy is matched to the patient and manufactured to order. As in the case of CAR-T therapy, the deep pockets and logistical expertise of one or more global pharmaceutical companies will be essential to clinical adoption.

Photo credit: Credit: National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Updated 30th June 2018

Recommended (and free to access) article on the current status and challenges facing phage therapy published in Nature Biotechnology.

Phage therapy’s latest makeover.Schmidt, C.  Nature Biotechnology volume 37, pages 581–586 (2019).  http://tinyurl.com/y4b7ka6f 

Updated 23rd June 2018

A phage therapy centre,The Center for Innovative Phage Applications and Therapeutics,   has been opened in the US within the School of Medicine, University of California (San Diego). The Center will undertake clinical trials and sourcing the appropriate phage for individual treatments. First phage therapy center in the U.S. signals growing acceptance. Boodman. E. STAT online 21st June 2018. http://tinyurl.com/y7x6xplo.

AmpliPhi Presents Case Study of Bacteriophage Used to Treat Drug Resistant Infection in Cystic Fibrosis Patient. Company news release online 7^th June 2018. http://tinyurl.com/ychkoy8y.

Return of the phages - a forgotten remedy makes a comeback. Tsang J. American Society for Microbiology blog. Online 5^th March 2018. http://tinyurl.com/ybj77ugp.