Overuse of antibiotics has accelerated the development of bacterial resistance to conventional drugs, a global health crisis projected to result in more than 10 million deaths annually by 2050. The multidrug-resistant bacterium Pseudomonas aeruginosa accounts for approximately one-fifth of hospital-acquired pneumonia cases and is associated with severe illness and increased mortality.
Nitric oxide is a therapeutic gas that researchers at Massachusetts General Hospital, a founding member of the Mass General Brigham healthcare system, helped establish as a life-saving therapy for hundreds of thousands of newborns with congenital heart disease. Nearly 30 years later, investigators from the same laboratory at Mass General Brigham report that high-dose inhaled nitric oxide (iNO) demonstrates potential antimicrobial activity in preclinical models and is safe and feasible in early human studies, supporting further clinical investigation. The findings are published in Science Translational Medicine.
"This study provides a translational foundation rather than a definitive clinical solution," said first author Binglan Yu, PhD, of the Mass General Brigham Department of Anesthesia, Critical Care and Pain Medicine. "Our findings demonstrate strong preclinical antipseudomonal effects together with reassuring human safety data."
"These results justify the careful design of phase 2 and phase 3 clinical trials to formally assess clinical efficacy," added co-first author Bijan Safaee Fakhr, MD, also of the MGB Department of Anesthesia, Critical Care and Pain Medicine.
In the study, researchers first demonstrated dose-dependent killing of Pseudomonas aeruginosa using nitric oxide-releasing compounds in vitro. They then showed that pigs with experimental P. aeruginosa pneumonia treated with high-dose iNO (300 parts per million) exhibited reduced bacterial burden, along with improved oxygenation and other markers of lung infection, compared with untreated animals.
To assess feasibility and safety in humans, the investigators evaluated repeated high-dose iNO exposure in 10 healthy volunteers and two critically ill patients affected by multidrug-resistant bacterial infection. The treatment was well tolerated, with no serious safety concerns observed. A retrospective analysis of patients who received high-dose iNO in clinical settings, mostly during the COVID-19 pandemic, further supported the safety profile of this approach.
"These results suggest a promising strategy that could complement existing treatments," said senior author Lorenzo Berra, MD, of the MGB Department of Anesthesia, Critical Care and Pain Medicine. "However, rigorous clinical trials are essential before this approach can be considered for routine clinical use."
Authorship: In addition to Binglan Yu, Bijan Safaee Fakhr, and Lorenzo Berra, Mass General Brigham authors include Lynn Bry, Angela Shih, Hatus V. Wanderley, Ryan W. Carroll, Dario Winterton, Talisa Buehl, Mohamed Okda, Giovanni Bruno, Eizo Marutani, Stefano Cenci, Kyle J Medeiros, Regina Villalobos, Stefano Spina, Cristina Mietto, Edward A Bittner, Maurizio Cereda, Mary L Delaney, Paolo Cadringher, Carolyn LaVita, and Fumito Ichinose. Additional authors include Yue Dai, Dennis J. Stuehr, and Pankaj Arora.
Disclosures: Berra, Yu, and Carroll are co-inventors on a filed patent (#US2023/0201514A1) entitled "Systems and methods for nitric oxide generation and treatment."
Funding: This study was supported by grants from Philanthropy at the Lung Rescue Team/MGH, Masimo Corp. (#2023A008593) to Berra, Mallinckrodt Pharmaceuticals (IIR-USA-011279) to Berra, Sundry funds at MGH, laboratory funds of the Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care and Pain Medicine at MGH, Reginald Jenney Endowment Chair at Harvard Medical School to Berra. In kind devices were offered by Mallinckrodt Pharmaceuticals, Masimo Corp. and Third Pole Therapeutics. Studies in the Massachusetts Host-Microbiome Center were supported by National Institute of Diabetes, Digestive and Kidney Diseases (P30 DK034854) and the Massachusetts Life Sciences Center (MLSC) to Bry. Stuehr was supported by National Institutes of Health Grants (R01 GM148664).
Paper cited: Yu B et al. "Inhaled nitric oxide at 300 ppm treats multidrug-resistant Pseudomonas pneumonia in swine and is safe in humans" Science Translational Medicine DOI:10.1126/scitranslmed.ady2646
