Treatment of Antibiotic-Resistant Infections: Back to the Future of Therapies

The closing plenary at the 2018 annual ID Week 2018, held in San Francisco, California, took a decidedly personal turn in addressing the re-emergence of phage therapy to treat antibiotic-resistant bacterial infections. The panel of presenters included Steffanie Strathdee, PhD, department of medicine, University of California San Diego (UCSD), and her husband Thomas Patterson, PhD, a professor of psychiatry at UCSD.

As well as being a research team in the study of HIV infection in marginalized populations, they are the reason phage treatment of resistant infections has been kick-started after nearly a century of dormancy. Their involvement is not rooted in professional interest, but rather the last-ditch, nothing-left-to-lose use of phage therapy to save the life of Dr. Patterson.

Their story has splashed across the popular press, including Mother Jones,¹ Time,² BuzzFeed News,³ Huffington Post,⁴ been the subject of a TEDx talk delivered by Dr. Strathdee,, a research article,⁶ and a memoir.⁷ Dr. Patterson acquired an Acinetobacter baumannii infection that became virtually pan-resistant and deadly. Grasping for straws, Dr. Strathdee stumbled upon the historical descriptions of the success of bacteriophages to treat bacterial infections.

The strategy had fallen out of favor for reasons that had more to do with personal biases against the approach and the advent of the penicillin era rather than because the approach did not work.

In a heroic mustering of expertise and support from the US Food and Drug Administration, a phage preparation was formulated and injected. When therapy began, Dr. Patterson was comatose and in dire shape. Within 4 days, his condition had improved and the resistance to minocycline had reversed, allowing this antibiotic to be added to the phage therapy. (Subsequent scrutiny of the therapy revealed the therapeutic synergy between the phage and minomycin.) Within a week, Dr. Patterson had regained consciousness and was responsive. Recovery was eventful and prolonged, but 8 months later he went home.

The plenary used this odyssey as a springboard to a broader consideration of the re-emergence of phage therapy and how this time around, the approach may gain traction as a go-to strategy for the treatment of bacterial infections.

“We need to think about phage therapy the way we have approached the development of antibiotics in striving to develop bacteriophage therapeutics,” said Robert Schooley, MD, an infectious disease specialist at UCSD, who was a principal member of the team that saved Dr. Patterson’s life. This reasoned thinking calls for answers to questions concerning the dose used, dosing frequency, optimal route of administration, pharmacokinetics and pharmacodynamics, and toxicities.

In Dr. Patterson’s case, these decisions were as reasoned as they could be, given that the clinicians were improvising on the fly. Efforts were made to purify the phage preparation to minimize the risk of introducing endotoxin, for example.

Other facets that were likely affected by the phage that drove the success of the treatment were the reduction of the capsule that is produced by A baumannii, disruption of the surface-adherent biofilms that formed, and enhancement of pathogen-specific immune responses.

“Tom’s case was extremely gratifying. But at the end of the day, he was only one more anecdote in a field that has been plagued for a century with empiric descriptions of success or failure with little rigorous clinical and translational research,” said Dr. Schooley.

Thankfully, Dr. Patterson has not become a blip-in-time anecdote. His treatment success combined with the concurrent research interest of other groups in phage therapy has led to some other attempts to rectify bacterial illnesses in patients. They have mostly been successful. One clinical trial has been done. Although less than successful, aspects of phage preparation and dosing that hampered efficacy were identified. Thus, the trial may ultimately prove valuable in informing future efforts.

Still, the science is in its infancy. Challenges concerning lysogeny and selection of phage-resistant bacteria remain to be overcome. “We have anecdotes and empiric observations, and basic knowledge bacteriophages. But, we lack a rigorous understanding of the clinical utility of phages,” explained Dr. Schooley.

Which patients are most likely to benefit from phage therapy? Likely candidates include those with multidrug-resistant infections that are disseminated or localized (in the lungs, urinary tract, and skin), those with infections of implanted prosthetic devices, prostate infections, and cardiac valvular vegetations. More candidates will surely be identified with time.

Critical issues that need to be addressed for clinical development include methods to characterize phage activity in vitro, fixed versus custom phage cocktails, optimizing the nuts and bolts of treatment, and understanding the synergies that exist with antibiotics so that the phage-antibiotic combo can be unleashed.

“So where do we go from here?” posited Dr. Schooley. “We treat phage therapy like we have treated antibiotic development. We execute a series of rigorously designed prospective clinical trials using traditional approaches used to evaluate any new antimicrobial agent.”

Phage therapy really is a back-to-the-future scenario. But, compared with a century ago, there is a much better understanding of issues related to host range, greatly improved production technology, the capability to engineer phages, and a better understanding of phage pharmacologic behavior.

The stage may finally be set for the phage therapy era for recalcitrant bacterial infections. And for other uses as well—this past February, the FDA approved a clinical trial designed to treat Crohn’s disease with phage therapy.

REFERENCES:

1. McKenna M. He Was Dying. Antibiotics Weren’t Working. Then Doctors Tried a Forgotten Treatment. Mother Jones website. motherjones.com/environment/2018/05/the-best-viral-news-youll-ever-read-antibiotic-resistance-phage-therapy-bacteriophage-virus/. Published May 2018. Accessed October 7, 2018.
2. Sifferlin A. Superbugs Are Nearly Impossible to Fight. This Last-Resort Medical Treatment Offers Hope. Time. time.com/5068513/superbugs-are-nearly-impossible-to-fight/. Published December 18, 2017. Accessed October 7, 2018.
3. Ghorayshi A. Her Husband Was Dying From A Superbug. She Turned To Sewer Viruses Collected By The Navy. Buzzfeed. buzzfeednews.com/article/azeenghorayshi/navy-phage-viruses-for-antibiotics-crisis. Published May 6, 2017. Accessed October 7, 2018.
4. Weber, L. Sewage Saved This Man's Life. Someday It Could Save Yours. Huffington Post. huffpost.com/entry/antibiotic-resistant-superbugs-phage-therapy_n_5913414de4b05e1ca203f7d4. Published May 11, 2017. Accessed October 7, 2018.
5. Strathdee S. How Sewage Saved My Husband's Life from a Superbug | Steffanie Strathdee | TEDxNashville. https://www.youtube.com/watch?v=AbAZU8FqzX4. Published October 17, 2017. Accessed October 7, 2018.
6. Schooley RT, Biswas B, Gill JJ, et al. Development and Use of Personalized Bacteriophage-Based Therapeutic Cocktails To Treat a Patient with a Disseminated Resistant Acinetobacter baumannii Infection. Antimicrob Agents Chemother 2017;61:e00954-17. doi: 10.1128/AAC.00954-17.
7. Strathdee S, Patterson T, Barker T. THE PERFECT PREDATOR. A Scientist's Race to Save Her Husband from a Deadly Superbug: A Memoir. https://www.hachettebooks.com/titles/steffanie-strathdee/the-perfect-predator/9780316418089/\.

DISCLOSURES

Steffanie Strathdee, PHD: Adaptive Phage Therapeutics; AmpliPhi BioScienScientifces

Thomas Patterson, PHD: Adaptive Phage Therapeutics; AmpliPhi BioSciences

Robert Schooley, MD: Scientific advisor to AmplPhi (uncompensated)

PRESENTATIONS

Closing Plenary

From Science Fiction to Clinical Trials: The Use of Phage to Treat Antibiotic Resistant Infections

Brian Hoyle, PhD, is a medical and science writer and editor from Halifax, Nova Scotia, Canada. He has been a full-time freelance writer/editor for over 15 years. Prior to that, he was a research microbiologist and lab manager of a provincial government water testing lab. He can be reached at hoyle@square-rainbow.com.