Azithromycin to prevent BPD in ureaplasma-infected preterms.

描述（由申请人提供）：携带生殖道支原体（细小脲原体和解脲原体）的早产儿呼吸道持续定植是慢性肺部疾病支气管肺发育不良（BPD）发展的重要危险因素(1)，并可能导致生命第一年的不良肺部结局。目前尚无治疗感染早产儿脲原体的有效方法。我们的长期目标是开发根除早产儿呼吸道脲原体的治疗方法，预防或改善脲原体介导的肺损伤。azalide抗生素azithromcyin （AZI）具有免疫调节特性，使其成为预防早产儿ureapplasma介导的肺损伤的理想候选药物。AZI 1)在小鼠肺损伤模型中抑制中性粒细胞内流和趋化剂/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)；3)优先集中在肺泡上皮内层液和巨噬细胞中（6,7）。在新生小鼠脲原体感染模型中，AZI而不是红霉素治疗提高了存活率并减少了肺部炎症(8)。我们假设AZI治疗将通过加速病原体清除和/或下调肺部炎症反应来预防尿原体感染早产儿的BPD。目前，我们正在进行一项I期开放标签药代动力学（PK）研究，研究10 mg/kg和20 mg/kg静脉注射AZI对24-28周妊娠期尿素原体呼吸道定殖和BPD高风险早产儿的单剂量药代动力学、安全性、耐受性和生物学效应。对于10 mg/kg单剂量样品，外周室清除率和容积（V2）按体重异速缩放的双室结构模型最能描述AZI在早产儿体内的PK。单剂量方案是安全的，但不足以根除脲原体或抑制肺部炎症反应。药代动力学模拟表明，即使多次给药10 mg/kg AZI也不足以将脲原体分离株AZI血浆浓度维持在MIC50以上。该提案的具体目标将涉及AZI在早产儿人群中进行III期安全性和有效性试验的下一步准备工作。本研究将1)对妊娠24-28周、脲原体呼吸道定植和BPD发展高风险的机械通气早产儿IV AZI的多剂量药代动力学（PK）、耐受性、安全性和生物学效应进行研究；2)开展多中心、随机、双盲、安慰剂对照的IIb期临床试验，以确定静脉注射AZI多剂量疗程根除可能导致生生性BPD的呼吸道脲原体感染的安全性和微生物学有效性；3)比较AZI与安慰剂治疗的婴儿在经后36周和调整后6个月时的肺结局。

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. PUBLIC HEALTH RELEVANCE: Babies who are born prematurely with an infection with the bacteria Ureaplasma frequently develop a chronic lung condition caled bronchopulmonary dysplasia (BPD)(1). Currently, there are no effective therapies to treat this infection or prevent BPD in infected infants. This study will 1) evaluate the safety of and how the body processes the antibiotic azithromycin, 2) determine the effectiveness of a 3-day course of azithromycin in eliminating Ureaplasma infection from the lungs of preterm infants, and 3) compare the lung health outcomes of the infants treated with azithromycin with the outcomes of placebo-treated infants.