Endotypes of Pseudomonas aeruginosa Infection in Bronchiectasis Are Associated with Inhaled Antibiotic Response: Results from Two Randomized, Double-Blind, Placebo-controlled Phase III Trials (ORBIT 3 and ORBIT 4).

Objectives: This study investigated if different microbial and inflammatory endotypes are linked to antibiotic response in patients with chronic Pseudomonas aeruginosa infection.

目的：本研究调查了不同的微生物和炎症表型是否与慢性铜绿假单胞菌感染患者的抗生素反应相关。

Methods: ORBIT-3 and ORBIT-4 were phase III trials of inhaled liposomal ciprofloxacin compared with placebo in patients with bronchiectasis with chronic P. aeruginosa infections.

方法：ORBIT-3 和 ORBIT-4 是两项 III 期临床试验，比较吸入脂质体环丙沙星与安慰剂在支气管扩张症患者中的疗效，这些患者伴有慢性铜绿假单胞菌感染。

Baseline sputum from the trials were analyzed by 16S rRNA sequencing (LoopSeq) (n = 377), proteomics (n = 164), and Olink (n = 117).

试验中的基线痰液样本通过16S rRNA测序（LoopSeq）（n = 377）、蛋白质组学（n = 164）和Olink（n = 117）进行了分析。

Relationships with clinical features and frequency of exacerbations during the trials were analyzed.

分析了临床特征与试验期间加重频率之间的关系。

Measurements and Main Results: Patients with P. aeruginosa infections demonstrated heterogeneous endotypes.

测量和主要结果：患有铜绿假单胞菌感染的患者表现出异质性的内型。

Reduced microbiota diversity was associated with exacerbation frequency (P = 0.021) and quality of life (P = 0.012).

微生物群多样性减少与加重频率(P = 0.021)和生活质量(P = 0.012)相关。

Increased exacerbations were associated with increased Pseudomonas abundance and neutrophilic inflammation; decreases in the relative abundance of commensals, including Rothia; and B-cell responses.

加重频率增加与铜绿假单胞菌丰度增加和中性粒细胞炎症增加有关；与共生菌相对丰度的减少有关，包括Rothia；以及B细胞反应。

Geographical differences were observed, with increased microbiota diversity and decreased neutrophilic inflammation in Central Europe.

观察到地理差异，中欧地区的微生物群多样性增加，中性粒细胞炎症减少。

Candidate biomarkers for treatment response were identified, including neutrophil elastase, LSP1, and Rothia relative abundance.

确定了治疗反应的候选生物标志物，包括中性粒细胞弹性蛋白酶、LSP1和Rothia相对丰度。

Before adjustment, treatment estimates of the two trials varied (ORBIT-3 rate ratio [RR], 0.85 [0.65-1.12], ORBIT-4 RR, 0.63 [0.48-0.82]).

调整前，两项试验的治疗估计值存在差异（ORBIT-3率比[RR]，0.85 [0.65-1.12]，ORBIT-4 RR，0.63 [0.48-0.82]）。

After linear discriminant analysis to adjust for microbiota profile and geographical region, the treatment estimates of ORBIT-3 (RR, 0.81 [0.54-1.22]) and ORBIT-4 (RR, 0.82 [0.56-1.22]) were similar and consistent with previous meta-analyses of inhaled antibiotics in bronchiectasis.

在进行线性判别分析以调整微生物群落特征和地理区域后，ORBIT-3（RR，0.81 [0.54-1.22]）和ORBIT-4（RR，0.82 [0.56-1.22]）的治疗估计值相似，并与之前关于支气管扩张症吸入抗生素的荟萃分析结果一致。

Conclusions: Patients with chronic P. aeruginosa have heterogeneous microbiota and inflammatory profiles, influencing antibiotic treatment responses in bronchiectasis.

结论：患有慢性铜绿假单胞菌感染的患者具有异质性的微生物群和炎症特征，这影响了支气管扩张症的抗生素治疗反应。

Future trials could be improved by patient stratification, including accounting for geographical differences and biomarkers to represent microbiota differences.

未来的试验可以通过患者分层来改进，包括考虑地理差异和代表微生物群差异的生物标志物。