Phage Used to Clear Antibiotic-Resistant Lung Infection for Cystic Fibrosis Patient

Using a virus to kill a bacterium may seem like going backward in medicine and harkens back to the early 20^th century when Julius Wagner-Juarreg used malaria to cure neurosyphilis (a feat that won him a Nobel Prize). Yet, bacteriophage (phage for short) has evolved to attack specific bacteria. In recent years, investigators have identified new wild-type phage strains and molecular mechanisms to enable researchers to engineer phage viruses to target specific bacteria.

Now, for the first time, researchers have successfully used bacteriophages to treat an antibiotic-resistant mycobacterial lung infection, clearing the way for a young patient with cystic fibrosis to receive a life-saving lung transplant. The successful use of phages to treat a Mycobacterium abscessus lung infection was reported in a case study published in Cell through an article titled, “Host and pathogen response to bacteriophage engineered against Mycobacterium abscessus lung infection.”

“We had tried unsuccessfully for years to clear the mycobacterial infection with a variety of antibiotics,” explained lead study investigator Jerry Nick, MD, director of the adult cystic fibrosis program at National Jewish Health. “When we used the bacteria’s own natural enemies, we were able to clear the infection, which resulted in a successful lung transplant.”

Cystic fibrosis is an inherited disease that causes a buildup of thick mucus in the lungs, leading to repeated bacterial infections that damage the lungs and can cause respiratory failure. Although new treatments have greatly improved the prognosis for people with cystic fibrosis, life expectancy remains significantly reduced.

Mycobacteria are a common and widespread genus of bacteria that can cause tuberculosis, leprosy, and nontuberculous mycobacterial (NTM) infections. Mycobacterium abscessus is a particularly aggressive and challenging NTM infection. Combinations of multiple antibiotics and treatment extending a year or longer are often unsuccessful. National Jewish Health has the most extensive adult cystic fibrosis program in the country and is a leading center for treating NTM infections.

“I am so grateful for the effort, persistence, and creativity of all the people who were involved in my treatment,” said Jarrod Johnson, recipient of the lung transplant. “I thought I was going to die. They have literally saved my life.”

Johnson is a 26-year-old cystic fibrosis patient who has suffered repeated lung infections throughout his life. As a child, he was admitted to various hospitals several times a year. As an adult, he experienced a rapid decline in his lung function following a persistent Mycobacterium abscessus infection over a six-year period and received several unsuccessful treatments. By 2020, his lung function had fallen below 30%. Without a lung transplant, doctors felt he was likely to die in only a few years.

Johnson had been refused transplants by three transplant centers, primarily because of his mycobacterial infection. Mycobacteria can spread from the lungs to the skin and other tissues, which can plague transplant recipients on immunosuppressive medications. Nick and his team at National Jewish Health considered phages as a potential treatment option. Johnson was hospitalized at Saint Joseph Hospital in Denver, where he spent more than 200 days the year before receiving phage treatment.

“Two mycobacteriophages were administered intravenously to a male with treatment-refractory Mycobacterium abscessus pulmonary infection and severe cystic fibrosis lung disease. The phages were engineered to enhance their capacity to lyse M. abscessus and were selected specifically as the most effective against the subject’s bacterial isolate,” the authors wrote. “In the setting of compassionate use, the evidence of phage-induced lysis was observed using molecular and metabolic assays combined with clinical assessments. M. abscessus isolates pre- and post-phage treatment demonstrated genetic stability, with a general decline in diversity and no increased resistance to phage or antibiotics. The anti-phage neutralizing antibody titers to one phage increased with time but did not prevent clinical improvement throughout the course of treatment.”

Phages are often specific to only a few types of bacteria. In 2016, Nick and his colleagues sent samples of the Mycobacterium abscessus from Johnson’s lungs in search of a phage that could kill the mycobacterium. Graham Hatfull, PhD, professor of biological sciences, University of Pittsburg, and his team screened dozens of phage candidates and identified two that efficiently killed the mycobacterium infecting Johnson’s lungs. These were genetically engineered to optimize their potential.

“This research can serve as a roadmap for future use of phages to treat patients with severe Mycobacterium abscessus lung infection and to save lives,” concluded Nick.