Phages Could Help When Antibiotics Fail

Cystic fibrosis outlook Phages could help when antibiotics fail

Bacteria-eating viruses are broadening the treatment landscape for people with drug-resistant infections. By Elizabeth Svoboda

fter more than a decade of drug- resistant infections, Ella Balasa’s options were running out. The bacterium Pseudomonas aeruginosa — common in people with cystic Afibrosis — had taken up long-term residence in Balasa’s lungs, eating away at the healthy lung tissue she had left. Balasa’s lung function dipped below 20% of normal, and at age 26, she depended on supplemental oxygen. “I needed oral antibiotics inhaled constantly,” Balasa says. “I knew that wasn’t sustainable.” Then Balasa, who lives in Richmond, Virginia, was interviewed for a documentary about bacteriophages, or phages for short. These specialized, bacteria-killing viruses showed promise of stamping out resistant infections like hers. Fascinated, Balasa looked up biologist Benjamin Chan, who was doing experimental phage treatments at Yale University in New Haven, Connect- icut, and asked him whether she could be

a candidate. PRESS/SHUTTERSTOCK RICHARD DREW/ASSOCIATED Cystic fibrosis researchers have long Ella Balasa inhales a phage treatment at Winchester Chest Clinic in New Haven, Connecticut. considered phages as a last resort — a fringe treatment only offered in Eastern Europe, the Maryland. Similar trials are scheduled to start the disease’s progression. long-time epicentre of phage research, and at other sites. In the meantime, laboratories The right phages can eradicate these a few other places. But the growing problem and providers continue to deliver custom resident lung bacteria. Phages attach to of antibiotic-resistant infections has spurred phage blends to people with cystic fibrosis- bacterial cell surfaces and inject their genetic fresh interest in the naturally occurring related infections. Phages are “a Hail Mary that’s material, hijacking the bacterium’s machin- viruses. Some doctors are now using phages here right now”, says Emily Kramer-Golinkoff, ery and forcing it to churn out thousands of to treat localized bacterial infections and to who has cystic fibrosis and is the founder of phages. The overstuffed bacterial cell then promote safe wound healing, although these the research-funding non-profit organiza- bursts, releasing the viruses. “Phages repli- treatments are not yet considered main- tion Emily’s Entourage in Merion Station, cate at the site of the infection and continue stream. Because phages can defeat bacteria Pennsylvania. “We have to be opportunistic to destroy bacteria,” says Greg Merril, chief when antibiotics fail, people with late-stage as a community, because people’s lives are on executive of biotechnology company Adaptive cystic fibrosis are increasingly seeking the the line.” Phage Therapeutics (APT) in Gaithersburg, treatment on a compassionate-use basis. Maryland. Because each phage attacks a A dedicated network of virologists, pulmo- Chronic infection specific strain of bacteria, the treatment does nologists, clinicians and others has stepped The hallmark of cystic fibrosis is thick not damage surrounding tissue. up to deliver, hunting down the right strains mucus that severely impedes breathing. Research on the use of phages in people of phage to treat patients’ infections. This mucus is also an ideal breeding ground with cystic fibrosis is promising. A study at The approach has piqued the interest of for antibiotic-resistant bacteria, including the US Naval Medical Research Center in major research centres and drug companies. strains of Pseudomonas, Mycobacterium and Silver Spring, Maryland, treated 13 people By the end of 2020, Armata Pharmaceuticals Burkholderia. with phages, 4 of whom had cystic fibrosis1. in Marina del Rey, California, expects to launch Such drug-resistant infections can linger In 11 of the 13, phages wiped out the targeted one of the first clinical trials of phage therapy for years and severely deplete lung function. bacteria. And a 15-year-old with cystic fibrosis for cystic fibrosis, funded by a US$5-mil- If highly advanced, they might also disqualify who was treated with a three-phage cocktail lion grant from the Cystic Fibrosis Founda- patients from getting a lung transplant — one improved markedly: not only did their drug- tion, a non-profit organization in Bethesda, of the only treatments that significantly delays resistant infection disappear, their lung and

liver function rebounded, too2. drew closer, her condition declined. “I had this Belgian government. “You take the ones that Although phage therapy is not a knockout really bad infection flare-up. I was really nerv- work, you can mix them,” says Pirnay. “You can punch against cystic fibrosis, it can be a way to ous,” she recalls. Worst-case scenarios flitted make a suspension for intravenous use, or a buy time. If a course of phages can dislodge a through her mind: what if the phage treatment nasal spray.” drug-resistant infection, a patient can recover caused her airways to swell and tighten? But APT is taking a similar tack in its clinical trial, enough to become a candidate for lung trans- she decided to go through with it anyway. She which is scheduled to start before the end of plant. Phages fit in “at the level of improving knew that the status quo — mega-doses of anti- the year. The company will draw on its own and prolonging life — taking down the bacterial biotics — would be ineffective. library to create personalized phage cocktails players that are really causing problems”, says for participants, and the trial will evaluate the microbiologist Jessica Sacher at the University Finding the right phage effectiveness of this approach. of Alberta in Edmonton, Canada. Despite her fears, Balasa knew she was lucky Safety must remain paramount along the A 25-year-old California woman, Mallory to find a researcher who could treat her. Hunt- way, says Elizabeth Burgener, who studies Smith, who had struggled for years with ing down the right phage can take months of microbial interactions in people with cystic drug-resistant Burkholderia cepacia infec- painstaking, unpaid detective work, even fibrosis at Stanford University in California. tions, was among the first people with cystic when Phage Directory is on hand to move Before approval, researchers will continue to fibrosis to get phage therapy in the United things along. Of 260 patients requesting phage assess phages’ long-term effects in early recip- States. Her father, Mark Smith, reached out therapy at a Belgian hospital between 2013 ients — monitoring whether the viruses shift to a handful of phage scientists, including and 2018, about half had to be turned down the overall bacterial balance in the lungs, for epidemiologist Steffanie Strathdee at the because the hospital did not have the right instance, and whether they cause swelling in University of California, San Diego. In Novem- phages3. “Cystic fibrosis patients really want infected airways. ber 2017, Strathdee asked researchers on this, and they want it now,” Strathdee says. Twitter whether they had a phage strain that “Sometimes patients and their loved ones are Life-changing worked on B. cepacia. angry that we can’t help them.” On 17 January 2019, Ella Balasa inhaled her Strathdee found a match for the bac To streamline the process of patient–phage first dose of phages through a nebulizer in a terium, but not in time: Mallory’s disease was matching, some researchers are building Yale clinic room. Seven days later, she hadn’t so advanced that she died before the phages standardized phage libraries. Phage Direc- noticed any improvement in her symptoms. could work. Still, an autopsy showed they had tory is compiling an open-access database Her regular physician issued a discourag- already started to deplete Mallory’s bacterial that indexes collections around the world, ing assessment of the treatment when she colonies, convincing Strathdee that phage and in 2019, researchers at the Baylor College returned to Richmond. “He said, ‘Obviously it’s therapy could be a huge boon for other people of Medicine in Houston, Texas, reported that not doing much for you. You’re probably going with cystic fibrosis. Under Strathdee’s leader- they had created libraries that work against to need a transplant’,” remembers Balasa. ship, the university launched the Center for three common pathogens4. In March, the US A few days later, when Balasa was at Duke Innovative Phage Applications and Therapeu- Food and Drug Administration approved APT’s University in Durham, North Carolina, for a tics (IPATH) in 2018, with cystic fibrosis as one application to create a comprehensive phage lung-transplant assessment, things started of its specialities. library called PhageBank. Sourcing phages to turn around. “I started coughing out all this in random labs or in nature “takes time”, dark, old mucus,” Balasa says. “It just started “Patients really want this, Strathdee says. “If you have a phage library, it’s coming out.” From past experience, she knew like a giant walk-in cooler.” that meant her infection was clearing. She and they want it now.” Another obstacle is that phage therapy also began to recover her strength — before doesn’t always fit into a standard clinical- the treatment, she had felt too weak even to Along with Phage Directory, a non-profit trial framework. In most drug trials, each wash her hair. Chan soon confirmed through organization in Atlanta, Georgia, that Sacher participant in the test group gets exactly bacterial cultures that her drug-resistant bac- co-founded, IPATH helps to match people who the same medication at the same dose. terium was indeed diminishing. have late-stage cystic fibrosis with phages that But that approach can be impractical with Although the phages helped to vanquish target their infections. When a patient needs phages. In cystic fibrosis, many people’s Balasa’s infection, they could not repair her phages for an antibiotic-resistant infection, drug-resistant infections are highly unusual, tissue damage. Her lung function now hovers an e-mail or social-media request goes out to requiring physicians to create custom phage at about 25% of normal. Still, Chan’s treatment dozens of research labs. These labs scan their preparations. helped to stabilize her condition enough that phage collections to see whether they have the Armata Pharmaceuticals’ upcoming phage she postponed her lung transplant and began right phage to destroy the person’s bacterium. trial sidesteps this issue by using a cocktail of Trikafta drug therapy instead (see page S2). Once a lab finds the ideal phage, technicians phages that target only P. aeruginosa. Other “Cutting out those severe infections,” Balasa grow billions of the viruses and ship them out. researchers are pursuing less-conventional says, “has changed my life.” As phage research So far, Phage Directory has coordinated phage routes. At the behest of molecular biolo- and trials proceed, she hopes others with sourcing for seven or eight patients. Others gist Jean-Paul Pirnay at the Queen Astrid cystic fibrosis will be able to say the same. have secured phages through independent Military Hospital in Brussels, Belgian regula- arrangements with labs elsewhere. tory authorities now allow phages to be used Elizabeth Svoboda is a freelance writer in San After hearing from Balasa, Chan told her in what Pirnay calls “magistral preparations”. Jose, California. he would take on her case. He had phages at This means pharmacists can legally create Yale that would combat the P. aeruginosa in custom phage blends for individual patients, 1. Duplessis, C. A. et al. J. Intens. Crit. Care 5, 11 (2019). 2. Dedrick, R. M. et al. Nature Med. 25, 730–733 (2019). her lungs, and Balasa scheduled a trip to New drawing from a commercialized bank of 3. Djebara, S. et al. Viruses 11, 265 (2019). Haven to begin her treatment. But as the date phages that have been pre-approved by the 4. Gibson, S. B. et al. Front. Microbiol. 10, 2537 (2019).