Azithromycin To Prevent BPD In Ureaplasma-Infected Preterms

项目摘要：对过去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的独立危险因素。 这个应用程序解决了一个根本问题，即目前没有足够的关于 抗生素治疗的益处/风险比推荐预防BPD的治疗指南和长期 高危早产儿或确诊为解脲支原体感染的早产儿的不良肺部结局。我们的长- 学期目标是开发从早产儿呼吸道根除解脲支原体的治疗方法。 预防或改善解脲支原体介导的肺损伤。氮杂环素抗生素阿奇凝血素(AZM) 抗菌和免疫调节特性，使其成为预防 解脲支原体介导的肺损伤。我们进行了PK/PD研究，以表征人群的PK、安全性、 单次给药10 mg/kg和20 mg/kg及多次给药20 mg/kg的耐受性和生物效应 妊娠24-28周的新生儿是解脲支原体呼吸道定植的高危人群， 每桶。一个两室模型，所有参数都是根据体重异速测量的，最好地描述了 早产儿AZM的PK检测与单剂量组相比，20 mg/kg多剂量组有效 在剂量前定植的所有受试者中根除了解脲支原体。多剂量方案出现了 安全，没有死亡或严重的不良反应归因于药物。我们在此应用程序中的目标是 短程静脉滴注阿司匹林根除呼吸道感染的安全性和微生物学疗效 尿道支原体感染及其对改善短期(BPD)和长期肺和 早产儿的神经发育结局。中心假设是阿扎姆疗法将减少 加速病原体清除和/或促进解脲支原体感染早产儿的肺部发病率 下调肺部炎症反应。我们已经完成了80%的计划招生 目前20 mg/kg X3D IV的多中心、随机、双盲、安慰剂对照的IIb期临床试验 阿兹姆。此续期申请的具体目标将延长结果至24个月调整后的年龄和 将讨论下一步准备在早产期进行的AZM第三阶段安全性和有效性试验 人口。这项建议的具体目的是：1)确定其安全性和微生物学功效 静脉注射阿奇米松根除早产儿呼吸道解脲支原体感染2)潜力分析 AZM用于减少BPD和改善长期肺结局；以及3)评估AZM对 调整年龄22-26个月神经发育障碍的风险。拟议的研究是 意义重大，因为它将直接导致关于未来第三阶段安全性和有效性试验的决定 AZM在早产人群中的应用以及关于临床评估的循证建议 以及在早产人群中围产期获得性支原体呼吸道定植的管理。

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.