PROJECT SUMMARY/ABSTRACT Bronchopulmonary dysplasia (BPD), or chronic lung disease of prematurity, is among the most devastating complications of preterm birth. It affects half of surviving extremely preterm infants, is associated with life-long deficits in health and cognition, and carries enormous societal burden and cost. Strikingly, there are no drug therapies shown to improve outcomes for infants with BPD. Our research seeks to resolve this care gap. An abundance of data support a causal link between pathologic microbial invasion of the lower respiratory tract (LRT) and worsening of respiratory health in chronic lung illness. Our work, and others’, has shown that the presence of pathogenic Gram-negative rod (GNR) bacteria in the lungs of ventilator dependent very preterm infants with BPD is an independent risk factor for significant and enduring respiratory morbidity. Systemically administered antibiotics do not adequately penetrate the lung epithelial lining fluid to eradicate these bacteria. In contrast, inhaled antibiotics deliver drug directly to the site of infection, offering a safer and more effective alternative. Inhaled tobramycin, an aminoglycoside with potent anti-GNR activity, is now a benchmark therapy in cystic fibrosis, where lung infection by Pseudomonas aeruginosa (a common GNR pathogen in BPD) accelerates parenchymal lung damage, promotes decline in lung function, and contributes to early mortality. Emerging data also show benefit with inhaled tobramycin in other pediatric and adult chronic respiratory conditions plagued by difficult to treated respiratory pathogens. These data provide strong biological plausibility that inhaled tobramycin will benefit very preterm infants with BPD who have pathogenic GNR organisms cultured from the LRT. However, inhaled tobramycin is only FDA approved for use in patients 6 years and older. Whether the typical dose and duration of therapy used in older children is appropriate for infants is uncertain. To rigorously characterize the risks and benefits of inhaled tobramycin in very preterm infants with BPD, we must first identify a well-tolerated dose for investigation in this unique population. To obtain these essential data, we propose to conduct a 3+3 inter-patient, ascending dose phase 1 trial of inhaled tobramycin in ventilator dependent very preterm infants with BPD who have pathogenic GNR bacteria cultured from the LRT. This trial will investigate up to 4 different doses of inhaled tobramycin: 78mg, 150mg, 216mg, and 300mg (FDA approved dose), each administered every 12 hours for up to 14 days. This study will establish the preliminary dose tolerability, pharmacokinetic, and exploratory efficacy data needed to design and conduct the first, placebo-controlled, randomized trial of this promising drug therapy in very preterm infants with BPD. Collectively, our proposed studies of inhaled tobramycin are poised to identify the first drug therapy that improves long-term outcomes in this un...