Phase 1 trial of inhaled tobramycin in very preterm infants with bronchopulmonary dysplasia

项目摘要/摘要 支气管肺发育不良(BPD)，或早产儿慢性肺部疾病，是最具破坏性的疾病之一。 早产并发症。它影响到一半存活的极早产儿，与终生相关 造成健康和认知缺陷，并带来巨大的社会负担和成本。令人惊讶的是，没有毒品 治疗显示可以改善患有BPD的婴儿的预后。我们的研究试图解决这一护理差距。 大量数据支持下呼吸道病理性微生物入侵之间的因果联系 慢性肺部疾病的呼吸道(LRT)和呼吸健康恶化。我们和其他人的研究表明， 呼吸机依赖者肺内致病性革兰氏阴性杆菌的存在 患有BPD的早产儿是显著和持久的呼吸道疾病的独立危险因素。 全身应用抗生素不能充分穿透肺上皮衬里液以清除 这些细菌。相比之下，吸入抗生素将药物直接输送到感染部位，提供了一种更安全和 更有效的替代方案。吸入妥布霉素，一种具有强大的抗GNR活性的氨基糖苷类药物，现在是一种 囊性纤维化的基准治疗，肺部感染铜绿假单胞菌(一种常见的GNR BPD中的病原体)加速实质肺损伤，促进肺功能下降，并有助于 早期死亡率。新出现的数据也显示吸入妥布霉素对其他儿童和成人慢性疾病有好处 呼吸道疾病受到难以治疗的呼吸道病原体的困扰。这些数据提供了强有力的 吸入妥布霉素将使患有BPD的早产儿受益的生物学合理性 从LRT培养的致病GNR生物体。然而，吸入妥布霉素只被FDA批准用于 适用于6岁及以上的患者。年龄较大的儿童使用的典型治疗剂量和持续时间是 是否适合婴儿尚不确定。 为了严格描述吸入妥布霉素对患有BPD的早产儿的风险和益处，我们 必须首先确定一个耐受性良好的剂量，以便在这个独特的人群中进行研究。为了获得这些 基本数据，我们建议进行一个33个患者间的、剂量递增的妥布霉素吸入试验1期试验 患有BPD的呼吸机依赖型极早产儿的GNR致病细菌培养自 轻轨。这项试验将研究最多4种不同剂量的吸入妥布霉素：78 mg、150 mg、216 mg和300 mg (FDA批准的剂量)，每12小时给药一次，最多14天。这项研究将建立 初步剂量耐受性、药代动力学和探索性疗效数据需要设计和实施 首先，对患有BPD的早产儿进行这种有前景的药物治疗的安慰剂对照随机试验。 总而言之，我们提出的吸入妥布霉素的研究将确定第一种药物疗法 改善这种正在研究的疾病的长期结果。

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 under studied disease.