Inhaled nitric oxide at 300 ppm treats multidrug-resistant <i>Pseudomonas</i> pneumonia in swine and is safe in humans

Antibiotic resistance in respiratory infections is an escalating global concern that requires innovative antimicrobial approaches. <i>Pseudomonas aeruginosa</i> 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 <i>P. aeruginosa</i> infection. In vitro, <i>P. aeruginosa</i> exhibited a dose-dependent reduction when exposed to an NO donor. In a mechanically ventilated swine model of <i>P. aeruginosa</i> 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 <i>P. aeruginosa</i> pneumonia, warranting further clinical evaluation.