Inhaled nitric oxide at 300 ppm treats multidrug-resistant Pseudomonas pneumonia in swine and is safe in humans.

Antibiotic resistance in respiratory infections is an escalating global concern that requires innovative antimicrobial approaches. Pseudomonas aeruginosa is a common multidrug-resistant pathogen and a major cause of hospital-acquired pneumonia. Accumulating evidence suggests that, at high doses, inhaled nitric oxide (iNO) acts as a potent antimicrobial agent. This study evaluated the efficacy and safety of iNO at 300 parts per million (iNO300) as a treatment for P. aeruginosa infection. In vitro, P. aeruginosa exhibited a dose-dependent reduction when exposed to an NO donor. In a mechanically ventilated swine model of P. aeruginosa pneumonia, intermittent iNO300 therapy resulted in a two-log reduction in bacterial burden, improved oxygenation and lung compliance, and reduced histopathological lung injury. A phase 1 clinical trial in 10 healthy individuals confirmed the safety of intermittent iNO300 therapy with no adverse events. In two critically ill patients with multidrug-resistant bacteria, who were in the intensive care unit, iNO300 was well tolerated, demonstrating clinical feasibility. Long-term follow-up of patients exposed to high-dose iNO for more than 6 years revealed no adverse outcomes. Our findings establish iNO300 as a promising antimicrobial agent against P. aeruginosa pneumonia, warranting further clinical evaluation.