Can bacteria-slaying viruses defeat antibiotic-resistant infections? A new U.S. clinical center aims to find out | Science

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Can bacteria-slaying viruses defeat antibiotic-resistant infections? A new U.S. clinical center aims to find out | Science

Phages like these studding an Escherichia coli bacterium target specific bacteria, complicating their use in medicine.


One piece of good news can make all the difference. In the fight against antibiotic-resistant infections, a decades-old approach based on bacteria-slaying viruses called phages has been sidelined by technical hurdles, dogged by regulatory confusion, and largely ignored by drug developers in the West. But 2 years ago, researchers at the University of California, San Diego (UCSD), used phages to knock out an infection that nearly killed a colleague. Propelled by that success and a handful of others since, UCSD is now launching a clinical center to refine phage treatments and help companies bring them to market.

A first in North America, the center will initially consist of 16 UCSD researchers and physicians. It aims to be a proving ground for a treatment that has long been available in parts of Eastern Europe, but that still lacks the support of rigorous clinical trials. “There have been just a ton of failures and false starts,” says Paul Bollyky, a microbiologist and physician at Stanford University Medical Center in Palo Alto, California, who studies phages. “The fact that a major American medical center is going to set up an ongoing enterprise around phage therapy … that’s kind of a game changer for the field, at least in the United States.”

Turning phages—found in soil, water, and sewage—into treatments isn’t straightforward. Because each of the millions of phage strains in nature targets a specific bacterium, putting them to use means finding the specific phages that attack the menace at hand. Still, clinical centers overseas, in Georgia and Poland, have reported encouraging results with phages over the years. And the rise of antibiotic-resistant infections has prompted a handful of U.S. companies and research centers to reconsider the approach.

The case that mobilized the UCSD team hit close to home. In 2015, UCSD psychologist Tom Patterson was airlifted home after a vacation in Egypt when a drug-resistant strain of the bacterium Acinetobacter baumannii invaded his pancreas. As available antibiotics failed and Patterson fell into a coma, his wife, UCSD epidemiologist Steffanie Strathdee, launched an international effort to find strains of phage that might save him. After treatment with a variety of phages donated by San Diego–based biotech AmpliPhi Biosciences, Texas A&M University, and the U.S. Navy, Patterson made a dramatic recovery.

“Everybody’s been talking about this case,” Bollyky says. “Not only did he survive the treatment, which can’t be taken for granted, but he also got better, and miraculously so.” Patterson received some of the phages intravenously—an approach considered risky because toxins from bacteria used to grow the phages could linger in the mixture. His recovery helped allay safety fears, and it turned Strathdee into a self-described “phage wrangler,” who helped match other patients with the right mixture of experimental phages. Since her husband’s recovery, the UCSD team has successfully cleared infections in five more people with phage cocktails, under a U.S. Food and Drug Administration (FDA) process designed for emergencies where no approved treatments are available.

But a string of anecdotes does little to answer key scientific questions: What is the safest and most effective way to administer phages? How well do phages target the site of infection? How quickly are bacteria likely to develop resistance? “Those are the kinds of things you have to ask in structured clinical trials,” says Robert Schooley, a UCSD physician and infectious disease researcher who treated Patterson and oversaw the other recent cases.

So he and Strathdee proposed the new clinical center, which will launch with a 3-year, $1.2 million grant from UCSD. The Center for Innovative Phage Applications and Therapeutics (IPATH) won’t manufacture any phage treatments itself, but it will collaborate with companies and academic groups outside UCSD on multicenter clinical trials. IPATH will initially focus on treating patients with chronic, drug-resistant infections related to organ transplants, implanted devices such as pacemakers or joint replacements, and cystic fibrosis. Schooley is discussing possible trials with a team at the National Institute of Allergy and Infectious Diseases, and with two companies that have provided phages to patients at UCSD: AmpliPhi and Adaptive Phage Therapeutics (APT), based in Gaithersburg, Maryland, which has licensed the Navy’s phage collection.

Running phages through modern clinical testing has proved difficult in the past. A European Union–sponsored trial known as PhagoBurn was all but derailed by a series of setbacks. “It was not an ideal trial, let me say it like that,” says Jean-Paul Pirnay, a bioengineer at Queen Astrid Military Hospital in Brussels, one of the partners in PhagoBurn. A key obstacle was the fact that the trial targeted burn wounds, which often harbor multiple bacterial infections. That made it hard to test the effects of a phage therapy aimed at just one species. Designed to include 220 patients, the trial ultimately recruited only 27, and it has not yet published its results.

The anticipated trials at UCSD, on the other hand, will focus on patients with a single, known bacterial infection, Schooley says. But he admits it will still be tricky to design trials that isolate the effect of phages without withholding other potentially beneficial treatments, including antibiotics. (Ultimately, Schooley and many others expect phages to work in tandem with antibiotics—not to replace them.)

IPATH collaborators will also have to navigate a drug approval system suited to more conventional treatments. Because a phage cocktail will often have to be custom-designed for an individual, regulatory agencies may not have a single product to evaluate for safety and efficacy. But after initial talks with FDA, Greg Merril, APT’s CEO, is confident the agency will be flexible. He plans to seek approval for an entire library of phages—about 100 for each bacterial species—from which doctors could create a cocktail of one to five phages for a patient.

In the meantime, Strathdee says the UCSD team plans to keep securing phages for individual cases under FDA’s emergency pathway. She and Schooley already get several inquiries a week from patients and families fighting drug-resistant infections. “We hope to not send people with superbugs away, but to welcome them with open arms,” she says. “Right now, they don’t have anywhere to go.”

Pirnay, whose team finds and formulates phages to treat infections related to battlefield injuries, has a piece of advice for the UCSD group: “Be careful not to create too high an expectancy with the public,” he says. “Even when you do not say that you will be able to treat everything, you create a demand with desperate patients.”

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