TOBRAMYCIN ACCUMULATION IN THE RESPIRATORY SECRETIONS OF CF PATIENTS WITH REPE

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定是研究者机构。大多数囊性纤维化（CF）患者的进行性阻塞性肺疾病的特征是慢性支气管内铜绿假单胞菌感染。抗假单胞菌抗生素的吸入给药是一种有吸引力的治疗选择，因为能够将高浓度的抗生素递送到支气管腔内的感染部位，同时最大限度地减少全身吸收。CF患者使用雾化氨基糖苷类药物与肺功能改善、住院率降低和支气管内铜绿假单胞菌负荷降低相关（1，2）。吸入用妥布霉素溶液（TSI，TOBI，Chiron Corp.，西雅图，华盛顿州）被美国食品和药物管理局批准用于治疗CF患者的慢性铜绿假单胞菌感染。它通常被规定为在交替的每月周期中使用，每个周期包括300 mg TSI，每日两次，持续28天，随后停止治疗28天。使用配有Pulmo-aide压缩机的Pari LC Plus喷射雾化器给药。该给药方案用于TOBI的关键III期研究（2），尚未研究替代给药方案。拟定研究的目的是评估妥布霉素是否在患有轻度至中度肺部疾病的CF患者重复给予TSI后的呼吸道分泌物中蓄积。这将是第一项测量与TSI重复给药相关的痰液妥布霉素浓度的研究。将使用痰液诱导，以非侵入性方式获得比咳痰产生的更多的远端气道分泌物。还将测量痰液中的妥布霉素浓度，因为痰液咳痰是既往研究中测量妥布霉素浓度的标准方法。本研究的结果可能导致探索TSI的替代给药方案。如果有证据表明这些受试者重复给药后妥布霉素蓄积，未来的研究可能会研究降低给药频率（例如，每日一次）或持续时间短于28天。这是一项前瞻性初步研究，旨在测量TSI（300 mg，每日两次）28天疗程开始和结束时诱导痰和咳出痰中的妥布霉素浓度。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The progressive obstructive pulmonary disease in most patients with cystic fibrosis (CF) is characterized by chronic endobronchial infection with Pseudomonas aeruginosa. Inhaled administration of anti-pseudomonal antibiotics is an attractive therapeutic option because of the ability to deliver high antibiotic concentrations to the site of infection in the endobronchial space while minimizing systemic absorption. The use of aerosolized aminoglycosides in patients with CF has been associated with improvement in lung function, decreased frequency of hospitalizations, and decreased endobronchial burden of Pseudomonas aeruginosa (1,2). Tobramycin solution for inhalation (TSI, TOBI , Chiron Corp., Seattle, WA) is approved by the U.S. Food and Drug Administration for the treatment of chronic Pseudomonas aeruginosa infection in patients with CF. It is generally prescribed for use in alternate monthly cycles, each cycle consisting of 300 mg of TSI twice daily for 28 days, followed by 28 days off therapy. The medication is delivered using a Pari LC Plus jet nebulizer with a Pulmo-aide compressor. This dosing regimen was employed in the pivotal Phase III studies of TOBI (2), and alternative dosing regimens have not been investigated. The objective of the proposed research is to assess whether tobramycin accumulates in the respiratory secretions of CF patients with mild to moderate lung disease with repeated dosing of TSI. This will be the first study to measure sputum tobramycin concentrations associated with repeated administration of TSI. Sputum induction will be utilized in order to non-invasively obtain more distal airway secretions than those produced by expectoration. Tobramycin concentrations will also be measured in expectorated sputum, as sputum expectoration is the standard means by which tobramycin concentrations have been measured in prior studies. The results of this study may lead to exploration of alternative dosing regimens for TSI. If there is evidence of accumulation of tobramycin with repeated dosing in these subjects, future studies may investigate dosing less frequently (e.g., daily) or for a shorter duration than 28 days. This is a prospective pilot study to measure tobramycin concentrations in induced and expectorated sputum at the beginning and end of a 28-day course of TSI, 300 mg twice daily.