Published Time：

Bronchiectasis is an irreversible chronic airway inflammatory disease. In recent years, the incidence and prevalence of bronchiectasis have been gradually increasing worldwide. According to the epidemiological description in the 2021 "Expert Consensus on the Diagnosis and Treatment of Bronchiectasis in Chinese Adults," the incidence of bronchiectasis in the UK population increased to 31.1/100,000 by 2013, and the prevalence increased to 525.8/100,000; the incidence of bronchiectasis in the Spanish population in 2012 was approximately 48.1/100,000; and the prevalence of bronchiectasis in US adults was approximately 139/100,000. The results of an epidemiological telephone survey study in 2013 showed that the prevalence of bronchiectasis in China reached 1.2%, and the prevalence in men (1.5%) was higher than in women (1.1%), suggesting that bronchiectasis is a common disease in China, far exceeding the epidemiological levels in other countries.

PA is one of the most important pathogens infecting adult bronchiectasis patients. The mortality rate of bronchiectasis patients with PA colonization/infection is three times higher than that of patients without PA colonization/infection, and the risks of acute exacerbation and hospitalization are also significantly higher, placing a heavy burden on patients and the healthcare system. Effective clearance of PA colonization is crucial for slowing the progression of bronchiectasis. Intravenous or oral antibiotics are not suitable for long-term use due to the ease of developing drug resistance and systemic toxicity; nebulized inhaled antibiotics can significantly increase the effective concentration of drugs in the airways, reduce systemic exposure, and minimize the probability of bacterial resistance, making them an effective new option for the treatment of bronchiectasis abroad. Therefore, the "European Respiratory Society Guidelines for the Management of Bronchiectasis in Adults" and the "British Thoracic Society Guidelines for Bronchiectasis in Adults" both recommend that patients with chronic PA infection or colonization can use inhaled antibiotics for 3 months to promote PA clearance. The latest version of the expert consensus in China also recommends long-term treatment with nebulized inhaled antibiotics for patients with PA infection or colonization.

Currently, inhaled antibiotic treatment is still a blank in China. Internationally, although tobramycin inhalation solution has been marketed, it is only used to treat lung infections in patients with cystic fibrosis (a common autosomal recessive genetic disease common in Western countries but rare in Asian populations; lung clinical manifestations are highly similar to bronchiectasis). Both cystic fibrosis and bronchiectasis patients can experience recurrent infections due to PA colonization in the lungs. The mechanism of action of tobramycin inhalation solution for cystic fibrosis and bronchiectasis is the same, and the administration route and dosage are also the same. Therefore, this phase III study aimed to investigate the efficacy and safety of tobramycin inhalation solution (TIS) in treating bronchiectasis with PA infection in the Chinese population.

This clinical trial included 357 patients with bronchiectasis and PA infection, who were randomly assigned to the tobramycin group (167 cases) and the placebo group (172 cases). Both groups received basic treatment, including: 1) expectorant (ambroxol 30 mg, three times a day; those intolerant to ambroxol were changed to N-acetylcysteine 0.6 g, twice a day); 2) chest physical drainage once a day, 5 minutes each time. On this basis, the placebo group received 5 ml of saline, twice daily nebulization inhalation; the tobramycin group received TIS 300 mg/5 ml, twice daily nebulization inhalation. Both groups used the medication for 28 days and stopped for 28 days, for a total of two cycles of treatment, with a total study period of 16 weeks. The primary endpoints were the change in sputum PA load on day 29 after treatment and the change in the respiratory symptom dimension score of the bronchiectasis quality of life score (QOL-B-RSS score) from baseline.

The results showed that the tobramycin group showed superiority in both primary efficacy endpoints. Compared with the placebo group, the sputum PA load on day 29 after treatment in the tobramycin group was significantly lower than the baseline (mean: 2.50 vs. 0.76 Log10CFU/g, P<0.001), and the change in QOL-B-RSS score from baseline was significantly improved (mean: 8.48 vs. 0.56, P<0.001). The incidence of adverse events in the tobramycin group (81.6%) was comparable to that in the placebo group (81.5%), and the incidence of dyspnea and tachypnea in the tobramycin group was very low (only 2.2% and 1.1%, respectively), indicating that the probability of tobramycin inhalation solution inducing airway spasm is extremely low. Therefore, tobramycin inhalation solution can effectively reduce the PA load in the airways of bronchiectasis patients, improve PA clearance rate, significantly improve the quality of life of bronchiectasis patients, and has good safety and tolerability.

1. Changing the current situation where Chinese bronchiectasis patients have no nebulized antibiotics available: Tobramycin inhalation solution is the first nebulized inhaled antibiotic used to treat bronchiectasis in China and is a modified new drug specifically developed for Chinese patients. It fills the gap in inhaled treatment for Chinese bronchiectasis patients with PA infection.

2. The dual-endpoint setting makes the trial results better reflect the clinical benefits to patients: Unlike other clinical studies of inhaled antibiotics for bronchiectasis, this study is the first to integrate bacterial load reduction and quality of life improvement as primary endpoints. The QOL-B-RSS score can better reflect the improvement of the main respiratory symptoms (such as cough frequency, sputum volume, and purulence) in bronchiectasis patients after tobramycin inhalation solution administration, but quality of life evaluation has never been included as a primary endpoint in previous trials. This study has achieved the common goal of bacterial load reduction and quality of life improvement, the credibility of the trial results is high, and tobramycin inhalation treatment can truly benefit patients.

3. Providing new options for clinical antibacterial treatment: The dual-positive results of the phase III trial of tobramycin also provide new ideas for the treatment of other types of pneumonia with PA infection (such as ventilator-associated pneumonia with Pseudomonas aeruginosa infection).

Author Information:

First Authors: Guan Weijie (the First Affiliated Hospital of Guangzhou Medical University), Xu Jinfu (Shanghai Pulmonary Hospital), Luo Hong (the Second Xiangya Hospital of Central South University), Xu Xingxiang (Subei People's Hospital), Song Yuanlin (Zhongshan Hospital Affiliated to Fudan University), Ma Wanli (Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology)

Other Authors: Liang Zong'an (West China Hospital of Sichuan University), Liu Xuedong (Qingdao Municipal Hospital), Zhang Guojun (the First Affiliated Hospital of Zhengzhou University), Zhang Xiaoju (Henan Provincial People's Hospital), Li Rongkai (the First People's Hospital of Xinxiang), Zhu Shuyang (Affiliated Hospital of Xuzhou Medical University), Zhang Yi Jie (Huaihe Hospital of Henan University), Cai Xingjun (Hainan Provincial People's Hospital), Wei Liping (the Third Affiliated Hospital of Guangzhou Medical University), Tian Dongbo (Qingyuan People's Hospital), Zhao Hui (the Second Affiliated Hospital of Anhui Medical University), Chen Pingyan (Southern Medical University), Qu Jieming (Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine)