INHALED TOBRAMYCIN IN YOUNG CYSTIC FIBROSIS PATIENTS

本提案的目的是确定吸入性抗生素妥布霉素吸入溶液（TOBI）在患有囊性纤维化（CF）和有记录的铜绿假单胞菌（Pa）下呼吸道感染的婴幼儿中的短期微生物学疗效和安全性。由于PA的初始定植可发生在生命的前5年，因此人们越来越关注研究非常年幼儿童的抗假单胞菌治疗，其长期目标是延迟或预防导致不可逆肺部疾病的慢性感染。为了在该年龄组中测试抗感染疗法，需要通过直接下呼吸道采样来测定抗微生物效果，并将这些测量与替代标记物进行比较。目前的建议是第一个多中心研究吸入抗生素在幼儿CF和应作为一个范例，为未来的抗微生物治疗试验。选择TOBI是因为它是唯一获得FDA批准的吸入抗生素。尽管有大量的动物毒性和人体安全性数据，但尚未在6岁以下儿童中收集到安全性或有效性数据。具体而言，我们假设对下呼吸道Pa培养阳性的6岁以下CF儿童给予TOBI吸入治疗，每日两次，持续28天，将是安全的，并导致下呼吸道培养中平均Pa密度显著降低。我们的次要结局将评价抗生素治疗对下呼吸道炎症（细胞计数、中性粒细胞百分比、细胞因子、弹性蛋白酶活性）、下呼吸道微生物学替代标志物（口咽培养物、Pa外毒素A抗体）和临床状态（3-5岁受试者的体重增加、改良Shwachman评分和肺功能检查）的影响。我们建议在囊性纤维化基金会（CFF）资助的治疗药物开发网络（TDN）的七个中心内进行一项多中心、双盲、安慰剂对照的随机试验。98例Pa支气管肺泡灌洗（BAL）培养阳性的受试者将随机接受TOBI或安慰剂治疗，每日两次，持续28天。在治疗结束时，将重复BAL以定量Pa下气道密度。这项研究将为CF幼儿使用吸入性抗生素提供有价值的微生物学疗效和安全性数据，并将提供下呼吸道感染和炎症替代标志物的重要数据。

The purpose of this proposal is to determine the short-term microbiologic efficacy and safety of an inhaled antibiotic, tobramycin solution for inhalation (TOBI), in infants and young children with cystic fibrosis (CF) and documented Pseudomonas aeruginosa (Pa) lower airway infection. Because initial colonization with Pa can occur in the first 5 years of life, there is growing interest in investigating anti-pseudomonal therapies in very young children with the long-term goal of delaying or preventing chronic infection that contributes to irreversible lung disease. To test anti- infective therapies in this age group, there is a need to assay the anti- microbial effect by direct lower airway sampling, and to compare these measures with surrogate markers. The current proposal is the first multicenter study of inhaled antibiotics in young children with CF and should serve as a paradigm for future anti-microbial therapeutic trials. TOBI has been selected because it is the only inhaled antibiotic with FDA approval. Although extensive animal toxicity and human safety data are available, no safety or efficacy data have been collected in children less than 6 years of age. Specifically, we hypothesize that administration of TOBI for inhalation twice daily for 28 days to children less than six years of age with CF who are culture positive for Pa in their lower airways will be safe and result in a significant reduction in the mean Pa density in lower airway cultures. Our secondary outcomes will evaluate the effect of antibiotic therapy on lower airway inflammation (cell count, % neutrophils, cytokines, elastase activity), surrogate markers of lower airway microbiology (oropharyngeal cultures, antibodies to Pa exotoxin A), and clinical status (weight gain, modified Shwachman scores, and lung function tests in subjects 3-5 years of age). We propose to conduct a multicenter, double blind, placebo-controlled randomized trial within the seven centers comprising the Cystic Fibrosis Foundation (CFF) funded Therapeutics Development Network (TDN). Ninety eight subjects with bronchoalveolar lavage (BAL) cultures positive for Pa will be randomized to receive TOBI or placebo twice daily for 28 days. At the end of treatment, a BAL will be repeated to quantitate Pa lower airway density. This study will provide valuable microbiologic efficacy and safety data for use of inhaled antibiotics in young children with CF, and will provide important data on surrogate markers of lower airway infection and inflammation.