Azithromycin to prevent BPD in ureaplasma-infected preterms.

描述（由申请方提供）：生殖道支原体、微小脲原体和U.溶脲支原体是慢性肺部疾病支气管肺发育不良（BPD）发展的重要风险因素（1），并可能导致出生后第一年的不良肺部结局。目前尚无有效的治疗感染早产儿支原体的疗法。我们的长期目标是开发治疗方法，以根除早产儿呼吸道中的脲原体，预防或改善脲原体介导的肺损伤。氮杂内酯类抗生素阿奇霉素（AZI）具有免疫调节特性，使其成为预防早产儿脲原体介导的肺损伤的理想治疗药物。AZI 1）在鼠肺损伤模型中抑制嗜中性粒细胞流入和化学引诱物/细胞因子释放（2-4）; 2）在体外对临床脲原体分离株表现出比红霉素更高的效力（5）;和3）优先浓缩在肺泡上皮衬里液和巨噬细胞中（6，7）。在新生鼠脲原体感染模型中，AZI而不是红霉素治疗改善了存活率并减少了肺部炎症（8）。我们假设AZI治疗可通过加速病原体清除和/或下调肺部炎症反应来预防支原体感染早产儿的BPD。我们目前正在进行一项I期开放标签、药代动力学（PK）研究，其特征在于10 mg/kg和20 mg/kg IV AZI在机械通气的24-28周妊娠早产新生儿中的单次剂量PK、安全性、耐受性和生物学效应，所述早产新生儿处于支原体呼吸道定植和BPD的高风险中。对于10 mg/kg单次给药样品，具有清除率和外周室体积（V2）的二室结构模型根据体重异速生长比例最佳地描述了早产新生儿中AZI的PK。单次给药方案是安全的，但不足以根除支原体或抑制肺部炎症反应。药代动力学模拟表明，即使10 mg/kg AZI多次给药也不足以维持AZI血浆浓度高于脲原体分离株的MIC 50。本提案的具体目标将涉及准备在早产人群中进行AZI III期安全性和有效性试验的后续步骤。该提案将1）描述在妊娠24-28周、具有支原体属高风险的机械通气早产新生儿中IV AZI多次给药的药代动力学（PK）、耐受性、安全性和生物学效应。2）进行多中心、随机、双盲、安慰剂对照的IIb期临床试验，以确定静脉内AZI的多剂量疗程根除可能导致早产新生儿生理性BPD的呼吸道脲原体感染的安全性和微生物学功效; 3）比较用AZI与安慰剂治疗的婴儿在月经后36周和6个月校正年龄时的肺部结果。

DESCRIPTION (provided by applicant): Persistent respiratory tract colonization of preterm infants with the genital mycoplasma species, Ureaplasma parvum and U. urealyticum, is a significant risk factor for the development of the chronic lung disorder bronchopulmonary dysplasia (BPD) (1) and may contribute to adverse pulmonary outcomes in the first year of life. There are no current effective therapies for the treatment of Ureaplasma in infected preterm infants. 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 (AZI) has immunomodulatory properties that make it an ideal candidate for therapy to prevent Ureaplasma-mediated lung injury in preterm infants. AZI 1) inhibits neutrophil influx and chemoattractant/cytokine release in murine lung injury models (2-4); 2) exhibits higher potency than erythromycin against clinical Ureaplasma isolates in vitro (5); and 3) is preferentially concentrated in alveolar epithelial lining fluid and macrophages (6, 7). In a neonatal murine Ureaplasma infection model, AZI, but not erythromycin treatment, improved survival and reduced lung inflammation (8). We hypothesize that AZI therapy will prevent BPD in Ureaplasma-infected preterm infants by accelerating pathogen clearance and/or down- regulating the pulmonary inflammatory response. We are currently conducting a Phase I open-label, pharmacokinetic (PK) study characterizing the single dose PK, safety, tolerability, and biologic effects of 10 mg/kg and 20 mg/kg IV AZI in mechanically ventilated 24-28 wk gestation preterm neonates who are at high- risk for Ureaplasma respiratory tract colonization and BPD. For the 10 mg/kg single dose sample, a two- compartment structural model with the clearance and volume of peripheral compartment (V2) allometrically scaled on body weight best described the PK of AZI in preterm neonates. The single dose regimen was safe, but insufficient to eradicate Ureaplasma or to suppress pulmonary inflammatory responses. Pharmacokinetic simulations indicated that even multiple dose administration of 10 mg/kg AZI would be inadequate to maintain AZI plasma concentrations above the MIC50 for Ureaplasma isolates. The specific aims of this proposal wil address the next steps preparatory to Phase III safety and efficacy trials of AZI in the preterm population. This proposal will 1) characterize the multiple-dose pharmacokinetics (PK), tolerability, safety, and biologic effects of IV AZI in mechanically ventilated preterm neonates born 24-28 weeks gestation at high risk for Ureaplasma spp. respiratory tract colonization and subsequent development of BPD; 2) conduct a multicenter, randomized, double-blind, placebo-controlled Phase IIb clinical trial to determine the safety and microbiological efficacy of a multiple dose course of intravenous AZI to eradicate respiratory tract Ureaplasma infection that might lead to physiologic BPD in preterm neonates; and 3) compare the pulmonary outcomes at 36 wk postmenstrual age and 6 months adjusted age in infants treated with AZI vs placebo.