Undoing Antibiotic Resistance With Phage Therapy
By Deborah Borfitz
February 12, 2020 | Perhaps no academic institution has worked longer on the clinical application of phages than Yale University where research efforts are focused on using the pathogen-fighting viruses to re-sensitize bacteria to the antibiotics they’ve grown resistant to. “We’re hoping to drive evolution in the other direction to preserve our antibiotic arsenal for longer,” says Benjamin Chan, Ph.D., associate research scientist in the department of ecology and evolutionary biology, who maintains a large natural-phage library in the laboratory of Professor Paul Turner.
The goal is to use phages to eradicate an infection, Chan says. “But as a backup, we’re hopeful we can start using older antibiotics again, or at least extend the lifetime of the library.”
The approach has been tested with success to target a protein on the surface of the multi-drug resistant pathogen Pseudomonas aeruginosa, a frequent cause of nosocomial infections such as pneumonia, urinary tract infections, and bacteremia, Chan says.
When resistance develops, phage are prevented from entering the cell wall of the bacteria, he explains, but there’s a tradeoff. By down-regulating their virulence factor to avoid being infected by phage, bacteria also lose their ability to pump antibiotics back out.
Chan says he has been working with phages for the past decade and experimenting with them therapeutically for the last four years, much of it in collaboration with clinicians at Yale New Haven Hospital. Fourteen patients have been successfully treated with phages to date, all through the Emergency Investigational New Drug (EIND) application process of the Food and Drug Administration (FDA), and the pace is expected to escalate significantly in 2020.
Over the past six years, Chan has created a large library of natural phages able to kill 11 different bacterial targets. Compared to similar repositories around the world, he says, it is “not too far behind but not much ahead in terms of characterization.”
His phage collection, together with water samples from which they’re sourced, resides in an on-campus refrigerator. Test tube contents come from places that include a pig farm in Connecticut, sewage from Mexico and East Africa, and waterways in and around Haiti, he says.
The “exotic” samples are primarily for collaborations with scientists in other countries working on phage projects, he notes. “For cases treated in the U.S., we’ve isolated phages from America.”
The phages get shared, as needed, for treatment cocktails administered primarily at Yale and the Center for Innovative Phage Applications and Therapeutics at the University of California, San Diego. Yale has a dedicated group of phage therapy researchers, with an advisory board providing oversight, moving the university closer to having its own formal phage therapy center, says Chan.
Researchers here specialize in using one phage at a time, versus collectively in a cocktail, so they can more accurately predict antibiotic resistance and then switch to another phage, says Chan. Yale is believed to be the only institution to be taking this “ultra-personalized” virulence approach to phage treatment.
“We’re not opposed to phage cocktails,” says Chan, noting that they can quickly knock down an acute infection. “But if it’s a chronic infection, or one with a high risk of re-infection, we go the single approach because we can effectively engineer the infection microbiome.”
Major improvements in genetics and molecular biology have provided a way to sequence the genome of disease-causing bacteria to better understand how resistance develops and match multidrug-resistant pathogens to phages that can tamp down their virulence, he says.
Most patients get treated with a phage and antibiotics either simultaneously or sequentially, says Chan. In 2016, Yale first used phage therapeutically to treat a patient with a longstanding graft infection. The following year, it reversed an antibiotic-resistance lung infection for the first time in a 22-year-old patient with cystic fibrosis (CF) named Paige. Since then, says Chan, multiple other CF patients have been similarly treated.
As detailed in an online video, Paige acquired a lung infection early in 2017 that failed to respond to two rounds of antibiotics. Nine months later, with her lung function at 69%—the lung health of a 67-year-old—she was unable to even take a shower by herself. Phage therapy was a last-ditch idea presented to doctors by Paige’s father.
Chan matched Paige’s bacterial strain with a three-phage cocktail that in a matter of days turned a cloudy sample of mucus from her lungs clear, says Chan. The phages were then concentrated and Chan hand-delivered them in a cooler to a Lubbock hospital where they were administered via a nebulizer.
Remarkably, the treatment had no discernible side effects and Paige started feeling better almost immediately. Within 10 days, the bacteria in her lungs reverted to being drug-sensitive again, he says, and 10 months later her lung function was at 79% (aka “stable”) and she was treated with intravenous antibiotics. Today, her lung function is over 90%, he adds.
Cases typically come in as an emailed request from a physician or patient in a dire situation, Chan says. More physicians are taking phage therapy seriously because “the data we’re generating are looking pretty encouraging.”
Chan says he became interested in phages after working at a small company that studied phages for agricultural purposes. On a hunch that the “amazing little creatures” might be useful in human medicine, he started reading up on the century-old treatment approach and talking to a colleague from Georgia (the former Soviet country) where phage therapy is used broadly.
The U.S. has many phage researchers, says Chan. But phage therapy is “much more a niche” with no more than 10 groups experimenting with the approach at any level and less than half of those using it as an applied tool. By that yardstick, the medical potential of phage therapy is disproportionately large, he adds.
One of the biggest strides in phage therapy over the past decade is the fact that it is being used in patients at all, particularly in the U.S., says Chan. More clinical trials are also starting—notably, in France, Belgium, and The Netherlands. Physicians in Belgium can even prescribe phages before they’ve been tested in clinical trials and pharmacists can prepare customized phage cocktails, provided they follow a monograph on how they’re to be prepared and administered.
“We’re working on our compassionate use program and will hopefully open our first clinical trials this year,” says Chan. Adaptive Phage Therapeutics (APT) will manufacture phages for the clinical studies that Yale researchers have discovered and characterized under the terms of a December 2018 collaboration agreement.