Azithromycin in Cystic Fibrosis: Microbiologic and Functional Impact of Potent Anti-Pseudomonal Activity on Inflammation

试点摘要 囊性纤维化（CF）的临床过程的特征在于由以下因素触发的气道炎症周期： 细菌病原体如铜绿假单胞菌和其它革兰氏阴性杆菌（GNR）生物， 导致急性气道恶化和由于粘液堵塞而增加的气道阻塞。减少 通过物理清除和抗生素治疗减轻气道中的细菌负担仍然是 CF肺病的管理。多个疗程抗生素的累积效应不可避免地导致 多药耐药（MDR）微生物。因此，重要的是要确定新的治疗方法， CF中的GNR微生物，以降低导致MDR微生物的选择压力，并进行更多治疗 一旦MDR微生物形成，目前的建议是，儿童与P殖民。 铜绿假单胞菌患者每周接受三次阿奇霉素治疗，因为这种疗法已被证明具有抗炎作用 并减少肺部恶化。铜绿假单胞菌和其他GNR对阿奇霉素不敏感， 在传统细菌培养基中进行的测定。因此，可以得出结论，阿奇霉素 对铜绿假单胞菌没有直接的抗菌作用。然而，来自Lin和Nizet等人的最近数据（数据 从最初的加州大学圣地亚哥分校RPDP中心拨款支持产生）表明，阿奇霉素可能直接 在小鼠模型中的体内抗微生物作用，并且可以用于治疗高度耐药的GNR。所以针对本 试点研究，我们计划利用国家的最先进的能力骑士和多雷斯坦实验室，以更好地 了解CF患者每日使用阿奇霉素5天短疗程的微生物组和代谢组学变化 最近感染铜绿假单胞菌的患者。这是了解阿奇霉素未来用途的关键 减少MDR感染的发展，并作为针对MDR GNR的有效抗菌剂 感染.这将通过以下具体目标来实现：具体目标1将决定 每日阿奇霉素对铜绿假单胞菌定植CF患者的微生物学效应， 铜绿假单胞菌呼吸道分离株在真核细胞培养基中的体外敏感性， 呼吸道微生物组和微生物代谢物在奈特实验室。具体目标2将决定 阿奇霉素对CF受试者的代谢组学影响，同时评估炎症标志物的变化 确定药物水平和抗炎反应之间的关系。这次试点的成功 鉴于已组建的非常成功的团队：强大的新研究员Dr. Kathryn Akong，CF专家; John布拉德利博士，儿科传染病专家， 抗菌治疗以及儿科治疗的临床试验和FDA监管批准;乔治博士 萨库拉斯是尼泽特实验室的成人传染病专家，他参与了最初的体内小鼠实验， 阿奇霉素和GNRs的模型实验;以及世界知名的Rob Knight和Pieter Dorrestein博士， 微生物组学和代谢组学领域的专家。

Pilot Abstract The clinical course of cystic fibrosis (CF) is characterized by cycles of airway inflammation triggered by bacterial pathogens such as Pseudomonas aeruginosa and other Gram negative rod (GNR) organisms, leading to acute airway exacerbations and increased airway obstruction due to mucus plugging. Reducing the burden of bacteria in the airways by physical clearance and treatment with antibiotics remains the cornerstone of management of CF lung disease. The cumulative effects of multiple courses of antibiotics inevitably leads to multi-drug resistant (MDR) organisms. Thus, it is important to identify new therapeutic approaches that target GNR organisms in CF to reduce selective pressure that leads to MDR organisms and to have more treatment options once MDR organisms have developed. The current recommendation is that children colonized with P. aeruginosa receive azithromycin three time a week as this therapy has been shown to be anti-inflammatory and reduce pulmonary exacerbations. P. aeruginosa and other GNRs are non-susceptible to azithromycin in assays that are performed in traditional bacteriologic media. Thus, one would conclude that azithromycin does not have a direct antimicrobial effect on P. aeruginosa. However, recent data from Lin and Nizet et al (data generated from initial UC San Diego RPDP Center grant support) suggest that azithromycin may have direct antimicrobial effects in vivo in a murine model and could be used to treat highly resistant GNRs. Thus, in this pilot study we plan to harness state-of-the-art capabilities of the Knight and Dorrestein labs to better understand the microbiome and metabolomic changes of a short five day course of daily azithromycin in CF patients recently colonized with P. aeruginosa. This is key to understanding the future utility of azithromycin in decreasing the development of MDR infections and as a potent anti-microbial agent against MDR GNR infections. This will be achieved with the following Specific Aims: Specific Aim 1 will determine the microbiologic effects of daily azithromycin in CF subjects with P. aeruginosa colonizationby evaluating the in vitro sensitivities of P. aeruginosa respiratory isolates measured in eukaryotic cell culture media, and the respiratory microbiome and microbial metabolites in the Knight lab. Specific Aim 2 will determine the metabolomic effects of azithromycin in CF subjects by evaluating the change in inflammatory markers as well as determining the relationship between drug level and anti-inflammatory response. This success of this pilot project is assured given the highly successful team that has been assembled: the strong new investigator, Dr. Kathryn Akong, a CF specialist; Dr. John Bradley, a pediatric infectious disease specialist with expertise in antimicrobial therapies as well as clinical trials and FDA regulatory approval of pediatric therapies; Dr. George Sakoulas, an adult infectious disease expert in the Nizet lab who was involved in the original in vivo mouse model experiments of azithromycin and GNRs; and Drs. Rob Knight and Pieter Dorrestein, world-renowned experts in the field of microbiome and metabolomics, respectively.