Azithromycin to prevent BPD in ureaplasma-infected preterms.

描述(由申请人提供)：患有生殖器支原体、细小解脲支原体和解脲支原体的早产儿持续呼吸道定植是慢性肺疾病支气管肺发育不良(BPD)发展的重要危险因素(1)，并可能在出生第一年导致不利的肺结果。目前还没有有效的疗法来治疗感染早产儿的解脲支原体。我们的长期目标是开发治疗方法，根除早产儿呼吸道中的解脲支原体，预防或改善解脲支原体介导的肺损伤。氮杂环素(AZI)抗生素具有免疫调节特性，使其成为预防早产儿解脲支原体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/细胞因子的释放(2-4)；2)在体外对临床分离的解脲支原体显示出比红霉素更高的效力(5)；3)优先集中在肺泡上皮衬里液体和巨噬细胞(6，7)。在新生小鼠解脲支原体感染模型中，Azi而不是红霉素治疗可以提高存活率并减少肺部炎症(8)。我们假设Azi疗法将通过加速病原体清除和/或下调肺部炎症反应来预防解脲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，研究10 mg/kg和20 mg/kg静脉注射Azi对24-28周龄的早产儿的单剂量PK、安全性、耐受性和生物效应，这些早产儿是解脲支原体呼吸道定植和BPD的高危人群。对于10 mg/kg单次给药样品，外周间隙和体积(V2)随体重异速变化的两室结构模型最好地描述了早产儿AZI的PK。单次给药方案是安全的，但不足以根除解脲支原体或抑制肺部炎症反应。药代动力学模拟表明，即使多次注射10 mg/kg的Azi，也不足以将解脲支原体分离株的Azi血浆浓度维持在MIC50以上。这项提案的具体目标将涉及在早产人群中进行AZI第三阶段安全性和有效性试验的下一步准备工作。这项建议将1)表征静脉注射阿齐的多剂量药代动力学(PK)、耐受性、安全性和对早产儿的生物效应。这些研究包括：1)研究新生儿呼吸道定植和随后的BPD发展；2)进行一项多中心、随机、双盲、安慰剂对照的IIb期临床试验，以确定多剂量静脉注射AZI根除可能导致早产儿生理性BPD的呼吸道支原体感染的安全性和微生物学疗效；以及3)比较服用AZI和安慰剂的婴儿在36周后年龄和6个月调整年龄时的肺部结局。 公共卫生相关性：患有解脲支原体感染的早产婴儿经常发展为慢性肺部疾病，称为支气管肺发育不良(BPD)(1)。目前，还没有有效的治疗方法来治疗这种感染或预防感染婴儿的BPD。这项研究将1)评估抗生素阿奇霉素的安全性和身体处理方式，2)确定3天疗程的阿奇霉素在消除早产儿肺部解脲支原体感染方面的有效性，3)比较接受阿奇霉素治疗的婴儿和接受安慰剂治疗的婴儿的肺部健康结果。

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. 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.