Phage Therapy Clears Resistant Infection in CF Lung Transplant Patient

Phage Therapy Clears Resistant Infection in CF Lung Transplant Patient
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For the first time, bacteriophage therapy treated a boy with chronic and antibiotic-resistant Achromobacter bacteria infection following a double lung transplant due to cystic fibrosis (CF), a case study reported. 

The study, “A Case of Phage Therapy against Pandrug-Resistant Achromobacter xylosoxidans in a 12-Year-Old Lung-Transplanted Cystic Fibrosis Patient,” was published in the journal Viruses

Thick and sticky mucus often accumulates in the lungs of people with CF, creating an environment for bacterial growth that causes frequent chest infections. 

Antibiotics are the standard treatments for these infections, but some bacteria have become highly resistant to their action. 

Bacteriophages (or phages) are viruses that selectively infect and kill bacteria, while being otherwise harmless.  Used throughout the early 20th century, they fell out of favor in the mid-1900s as antibiotics became readily available. But as harmful pathogens develop resistance to these treatments, interest is again turning to phages as a potential way of treating multi-drug resistant infections, including those in CF patients. 

However, little data are available regarding the use of phages to treat infections, particularly with the bacteria Achromobacter xylosoxidans — a species that is increasingly being detected in the lungs of CF patients. 

Investigators at the University of Paris and colleagues described the case of a young CF patient, successfully given phage therapy for a post-transplant, antibiotic-resistant A. xylosoxidans infection. 

In March 2017, the 12-year-old boy received a CF-related double lung transplant. Before the transplant, he was infected with Pseudomonas aeruginosa, Aspergillus fumigatus, and A. xylosoxidans. After the transplant, he experienced acute kidney injury treated with dialysis, as well as pulmonary blood clots and a persistent airway infection with A. fumigatus.

He was discharged from the hospital in April with satisfactory lung status, and was prescribed immunosuppressive and antimicrobial medications. But within two months, he started on oxygen therapy due to progressive shortness of breath, cough, and increased sputum production. 

Inflammation and the presence of A. xylosoxidans were found after several bronchoalveolar lavages (BAL). BAL consists of injecting sterile saline through the bronchoscope into the lungs and then collecting the fluid and cells for analysis.

After an initial antibiotic treatment, the BAL samples remained positive for A. xylosoxidans and the boy still needed oxygen therapy. Subsequent lung samples were also positive for A. xylosoxidans, and his lung status did not improve. Phage therapy was proposed.

A cocktail of three types of phages that actively target a previously isolated A. xylosoxidans bacteria was administered in September 2017 by inhalation through a nebulizer, which changes a liquid medication to a mist. While the treatment was well-tolerated, the boy showed no clinical improvement and continued to test positive for A. xylosoxidans.

A second cocktail was given on Jan. 23, 2018, containing an additional phage-type to help improve its effectiveness. This cocktail was administered directly into the boy’s lung under general anesthesia. The next day, he was discharged and sent home with continued phage nebulization for 14 days.

Although his initial clinical status remained unchanged and still positive for A. xylosoxidans, his respiratory health slowly improved, and oxygen therapy was stopped a week later. For the next three months, his sputum culture remained positive for A. xylosoxidans but at low levels.

Tests conducted between August 2019 and April 2020 showed no A. xylosoxidans bacteria in BAL. A final lung function test within this study, given in October 2019,  showed improvement to normal levels. 

To further investigate the infection and treatment process, DNA analysis was applied to eight A. xylosoxidans samples isolated before, during, and after phage therapy. 

The overall similarity between the genome sequences of the eight isolates was greater than 99.60%, which was high. These findings suggested that these variants all originated from a single strain that colonized the boy years before the phage therapy. “[I]t is possible that some variants were present already before lung transplantation,” the team wrote.

Finally, each of the eight isolates’ susceptibility was tested against the second phage cocktail. Results showed that some A. xylosoxidans bacteria were susceptible to it, while others were not.

Two particular A. xylosoxidans strains were resistant to the phage cocktail and contained mutations, the other six isolated did not. These mutations were found in a gene that encoded for a protein recognized as a phage receptor, which may have been selected during phage therapy, leading to resistance. 

“In conclusion, we describe the first case of phage therapy for A. xylosoxidans lung infection in a lung-transplanted patient,” the researchers wrote. “Despite initial persisting airway colonization, the final clinical and microbiological outcome was favorable.” 

Steve holds a PhD in Biochemistry from the Faculty of Medicine at the University of Toronto, Canada. He worked as a medical scientist for 18 years, within both industry and academia, where his research focused on the discovery of new medicines to treat inflammatory disorders and infectious diseases. Steve recently stepped away from the lab and into science communications, where he’s helping make medical science information more accessible for everyone.
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Patrícia holds her PhD in Medical Microbiology and Infectious Diseases from the Leiden University Medical Center in Leiden, The Netherlands. She has studied Applied Biology at Universidade do Minho and was a postdoctoral research fellow at Instituto de Medicina Molecular in Lisbon, Portugal. Her work has been focused on molecular genetic traits of infectious agents such as viruses and parasites.

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Steve holds a PhD in Biochemistry from the Faculty of Medicine at the University of Toronto, Canada. He worked as a medical scientist for 18 years, within both industry and academia, where his research focused on the discovery of new medicines to treat inflammatory disorders and infectious diseases. Steve recently stepped away from the lab and into science communications, where he’s helping make medical science information more accessible for everyone.
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