TOBRAMYCIN ACCUMULATION IN THE RESPIRATORY SECRETIONS OF CF PATIENTS WITH REPE

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。大多数囊性纤维化(CF)患者的进行性阻塞性肺疾病以慢性支气管内铜绿假单胞菌感染为特征。吸入给予抗假单胞菌抗生素是一种有吸引力的治疗选择，因为它能够将高浓度的抗生素输送到支气管内间隙的感染部位，同时最大限度地减少全身吸收。在CF患者中使用雾化氨基糖苷类药物与改善肺功能、减少住院次数和减少铜绿假单胞菌(1，2)的支气管腔内负担有关。妥布霉素吸入溶液(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。它通常是每月交替使用的处方，每个周期包括300毫克的TSI，每天两次，持续28天，然后停药28天。药物是使用Pari LC Plus喷射式喷雾器和Pulmo-aide压缩机输送的。这种给药方案被用于TOBI(2)的关键III期研究，而替代给药方案还没有被研究过。这项拟议研究的目的是评估反复服用TSI的轻中度肺病患者的呼吸道分泌物中是否有妥布霉素积聚。这将是第一次测量与重复服用TSI相关的痰中妥布霉素浓度的研究。将使用诱导痰，以非侵入性地获得比咳痰产生的更多的远端呼吸道分泌物。托布霉素浓度也将在咳痰中测量，因为在以前的研究中，痰是测量妥布霉素浓度的标准方法。这项研究的结果可能会导致探索TSI的替代给药方案。如果有证据表明妥布霉素在这些受试者中反复给药积累，未来的研究可能会调查给药频率较低(例如，每天)或持续时间短于28天。这是一项前瞻性的先导性研究，每天两次，每次300毫克，在28天的TSI疗程开始和结束时，测量诱导痰和咳痰中妥布霉素的浓度。

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.