INHALED TOBRAMYCIN IN YOUNG CYSTIC FIBROSIS PATIENTS

这项建议的目的是确定吸入抗生素妥布霉素雾化溶液(TOBI)对患有囊性纤维化(CF)和已证实的铜绿假单胞菌(PA)下呼吸道感染的婴幼儿的短期微生物学疗效和安全性。由于PA的最初定植可能发生在生命的头5年，人们越来越有兴趣研究在非常年幼的儿童中使用抗假单胞菌疗法，长期目标是延迟或预防导致不可逆转的肺部疾病的慢性感染。为了在这个年龄段测试抗感染治疗，有必要通过直接下呼吸道采样来测试抗微生物效果，并将这些措施与替代标记物进行比较。目前的建议是第一个关于吸入性抗生素在患有CF的幼儿中的多中心研究，应该成为未来抗微生物治疗试验的范例。Tobi之所以被选中，是因为它是唯一获得FDA批准的吸入型抗生素。尽管有广泛的动物毒性和人类安全数据，但还没有收集到6岁以下儿童的安全性或有效性数据。具体地说，我们假设，对于下呼吸道PA培养阳性的6岁以下CF儿童，连续28天每天两次吸入TOBI将是安全的，并导致下呼吸道培养的平均PA浓度显著降低。我们的次要结果将评估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、弹力酶活性)、下呼吸道微生物替代标志物(口咽培养、PA外毒素A抗体)和临床状况(3-5岁受试者的体重增加、改良Shwachman评分和肺功能测试)的影响。我们建议在囊性纤维化基金会(CFF)资助的治疗发展网络(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名支气管肺泡灌洗(BAL)培养阳性的受试者将随机接受TOBI或安慰剂治疗，每天两次，持续28天。在治疗结束时，重复BAL以量化较低的气道密度。本研究将为吸入抗生素治疗儿童CF提供有价值的微生物学疗效和安全性数据，并将为下呼吸道感染和炎症的替代标记物提供重要数据。

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.