High-dose inhaled nitric oxide shows early promise against multi-drug-resistant Pseudomonas pneumonia

Researchers at Mass General Brigham have reported that intermittent, high-dose inhaled nitric oxide reduced bacterial burden and improved oxygenation in an animal model of Pseudomonas aeruginosa pneumonia, with early safety data in healthy volunteers and critically ill patients supporting further clinical trials

High-dose inhaled nitric oxide (NO) has demonstrated potential antimicrobial activity against Pseudomonas aeruginosa (P. aeruginosa) in laboratory and animal studies, with early-stage human data suggesting that the approach is feasible and well tolerated, according to researchers at Mass General Brigham in the United States.

The team reported dose-dependent killing of P. aeruginosa in vitro using NO-releasing compounds, before they tested high-dose inhaled NO in a large-animal model of bacterial pneumonia. In pigs with experimentally induced P. aeruginosa pneumonia, treatment with inhaled NO at 300 parts per million reduced bacterial burden and improved oxygenation, alongside favourable changes in other markers associated with lung infection, compared with untreated animals.

Antimicrobial resistance (AMR) has remained a major global health threat, driven in large part by excessive and misuse of antibiotics across human and veterinary medicine. While widely cited projections have suggested that drug-resistant infections could contribute to more than 10 million deaths per year by 2050, more recent modelling has indicated that annual deaths directly attributable to bacterial AMR could rise substantially by mid-century, with a far larger number of deaths linked to resistant infections overall.

P. aeruginosa has posed a particular challenge in hospitals because of its resistance to multiple antibiotics, its apparent ability to acquire additional resistance mechanisms, and capacity to cause severe disease in vulnerable patients. The pathogen is a recognised cause of hospital-acquired pneumonia, including ventilator-associated infections, and it has been associated with poorer clinical outcomes.

NO is best known as a signalling molecule in human physiology, but it also has broad antimicrobial effects under certain conditions, including nitrosative stress that can damage bacterial proteins, membranes and genetic material. Clinically, inhaled NO has served for decades as a targeted pulmonary vasodilator, particularly in neonatal care, because it can improve oxygenation with limited systemic effects when delivered via the lungs.

The Mass General Brigham investigators have now argued that a much higher, intermittent inhaled dose could provide an additional therapeutic option, particularly for multidrug-resistant pneumonia where antibiotic choices have become limited.

“This study provides a translational foundation rather than a definitive clinical solution,” said first author Dr. Binglan Yu 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,” she added.

To assess feasibility and safety in people, the researchers evaluated repeated exposure to high-dose inhaled NO in 10 healthy volunteers and two critically ill patients affected by multidrug-resistant bacterial infection. The treatment was well tolerated, and the team reported no serious safety concerns in this small cohort.

“These results justify the careful design of phase 2 and phase 3 clinical trials to formally assess clinical efficacy,” added co-first author Dr. Bijan Safaee Fakhr, also of the Mass General Brigham Department of Anesthesia, Critical Care and Pain Medicine.

They also carried out a retrospective analysis of patients who had received high-dose inhaled NO in clinical settings – largely during the COVID-19 pandemic – which further supported the safety profile of intermittent high-dose delivery. The authors concluded that the combined preclinical efficacy signals and early human safety data justified continued clinical development, with the next step likely to involve controlled trials that evaluate whether the approach can improve outcomes when added to standard antimicrobial therapy.

Although NO has attracted interest as an antimicrobial strategy for several years, the path to routine use has remained uncertain, in part because higher doses raise concerns about toxicity, including the potential to form nitrogen dioxide, as well as risks linked to methaemoglobinaemia which is a blood disorder in which haemoglobin becomes chemically altered so that it cannot carry oxygen effectively.

The latest report indicates that careful protocols, monitoring and intermittent dosing could help to mitigate these hazards, but larger studies will need to confirm safety in patients with severe lung disease, alongside robust measures of clinical benefit.

If future trials demonstrate efficacy, high-dose inhaled NO could provide clinicians with a supportive tool to tackle some of the most difficult hospital pneumonias, particularly in intensive care units where multidrug-resistant P. aeruginosa can prove hard to eradicate and rapid deterioration remains a constant threat.

For further reading please visit: 10.1126/scitranslmed.ady2646