Azithromycin To Prevent BPD In Ureaplasma-Infected Preterms

项目总结：过去30年临床研究的荟萃分析证实， 支原体呼吸道定植是支气管肺发育不良（BPD）的独立危险因素。 该申请解决了目前关于以下方面的数据不足的根本问题： 抗生素治疗的获益/风险比，以推荐预防BPD的治疗指南， 高危早产儿或确诊为支原体感染的早产儿的不良肺部结局。我们长久以来- 一个长期的目标是开发治疗方法，以消除早产儿呼吸道支原体 并预防或改善脲原体介导的肺损伤。氮杂内酯类抗生素azithrocyin（AXM）具有 抗微生物和免疫调节特性，使其成为预防 脲原体介导的肺损伤。我们进行了PK/PD研究，描述了群体PK、安全性、 10和20 mg/kg IV AZM单次给药和20 mg/kg多次给药的耐受性和生物学效应 妊娠24-28周的新生儿中3天，这些新生儿具有支原体呼吸道定植的最高风险， 波士顿警局所有参数均按体重异速生长比例缩放的2室模型最佳描述了 早产儿中AZM的PK。与单次给药组相比，20 mg/kg多次给药组有效 在给药前定植的所有受试者中根除了脲原体。多次给药方案出现了 安全，没有死亡或严重不良事件归因于药物。我们在此应用程序中的目标是 确定短期IV AZM根除呼吸道感染的安全性和微生物学疗效， 尿路支原体感染及其改善短期（BPD）和长期肺部和 早产儿的神经发育结果。中心假设是AZM治疗将减少 通过加速病原体清除和/或 下调肺部炎症反应。我们已经完成了80%的计划招生， 当前一项多中心、随机、双盲、安慰剂对照IIb期临床试验，20 mg/kg x3 d IV AZM。此更新申请的具体目标将延长结果至24个月调整年龄， 将讨论AZM在早产儿中的III期安全性和有效性试验的下一步准备工作 人口本提案的具体目标是：1）确定以下物质的安全性和微生物学功效： 静脉注射AZM根除早产儿呼吸道脲原体感染; 2）分析其潜在的 AZM减少BPD和改善长期肺结局; 3）评估AZM对 在22-26个月校正年龄时神经发育障碍的风险。拟议的研究是 重要的是，它将直接导致关于未来III期安全性和有效性试验的决定， AZM在早产儿人群中的应用以及关于临床评价的循证建议 和早产儿人群围产期获得性呼吸道脲原体定植的管理。

PROJECT SUMMARY: Meta-analyses of clinical studies over the past 30 years have confirmed Ureaplasma respiratory colonization as an independent risk factor for bronchopulmonary dysplasia (BPD). This application addresses the fundamental problem that there is currently insufficient data concerning the benefit/risk ratio of antibiotic therapy to recommend treatment guidelines to prevent BPD and long-term adverse pulmonary outcomes in preterm infants at-risk or with confirmed Ureaplasma infection. Our long- term objective is to develop therapies to eradicate Ureaplasma from the respiratory tract of preterm infants and prevent or ameliorate Ureaplasma-mediated lung injury. The azalide antibiotic azithromcyin (AZM) has antimicrobial and immunomodulatory properties that make it an ideal therapeutic candidate to prevent Ureaplasma-mediated lung injury. We conducted PK/PD studies characterizing the population PK, safety, tolerability, and biologic effects of a single dose of 10 and 20 mg/kg IV AZM and multiple dose 20 mg/kg x 3d in 24-28 wk gestation neonates who are at highest risk for Ureaplasma respiratory tract colonization and BPD. A 2-compartment model with all parameters allometrically scaled on body weight best described the PK of AZM in preterm neonates. Compared to the single dose groups, the 20 mg/kg multi-dose effectively eradicated Ureaplasma in all subjects who were colonized pre-dose. The multi-dose regimen appeared safe, with no deaths or serious adverse events attributed to the drug. Our objectives in this application are to determine the safety and microbiological efficacy of a short course of IV AZM to eradicate respiratory tract Ureaplasma infection and its' potential to improve short-term (BPD) and long-term pulmonary and neurodevelopmental outcomes in preterm neonates. The central hypothesis is that AZM therapy will reduce pulmonary morbidity in Ureaplasma-infected preterm infants by accelerating pathogen clearance and/or down-regulating the pulmonary inflammatory response. We have completed 80% planned enrollment in the current multicenter, randomized, double-blind, placebo-controlled Phase IIb clinical trial of 20 mg/kg x3d IV AZM. The specific aims of this renewal application will extend outcomes up to 24 months adjusted age and will address the next steps preparatory to Phase III safety and efficacy trials of AZM in the preterm population. The specific aims of this proposal are: 1) to determine the safety and microbiological efficacy of IV AZM to eradicate respiratory tract Ureaplasma infection in preterm neonates; 2) to analyze the potential of AZM to reduce BPD and improve long-term pulmonary outcomes; and 3) to assess the impact of AZM on the risk for neurodevelopmental impairment at 22-26 months adjusted age. The proposed research is significant because it will lead directly to decisions concerning future Phase III safety and efficacy trials of AZM in the preterm population and to evidence-based recommendations concerning the clinical evaluation and management of perinatally-acquired Ureaplasma respiratory colonization in the preterm population.