Binglan Yu, Bijan Safaee Fakhr, Lynn Bry, Angela Shih, H. Wanderley, Yue Dai, 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 J LaVita, Dennis J. Stuehr, Pankaj Arora, Fumito Ichinose, Lorenzo Berra
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 (iNO 300 ) 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 iNO 300 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 iNO 300 therapy with no adverse events. In two critically ill patients with multidrug-resistant bacteria, who were in the intensive care unit, iNO 300 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 iNO 300 as a promising antimicrobial agent against P. aeruginosa pneumonia, warranting further clinical evaluation.