The Efficacy and Safety of Inhaled Antibiotics for the Treatment of Bronchiectasis in Adults

Background Inhaled antibiotics are recommended conditionally by international bronchiectasis guidelines for the treatment of patients with bronchiectasis, but results of individual studies are inconsistent. A previous meta-analysis demonstrated promising results regarding the efficacy and safety of inhaled antibiotics in bronchiectasis. Subsequent publications have supplemented the existing body of evidence further in this area. Research Question To what extent do inhaled antibiotics demonstrate both efficacy and safety as a treatment option for adults with bronchiectasis? Study Design and Methods Systematic review and meta-analysis of randomized controlled trials of inhaled antibiotics in adult patients with bronchiectasis. We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and ClinicalTrials.gov for eligible studies. Studies were included if they enrolled adults with bronchiectasis diagnosed by CT imaging and had a treatment duration of at least 4 weeks. The primary end point was exacerbation frequency, with additional key efficacy end points including severe exacerbations, bacterial load, symptoms, quality of life, and FEV1. Data were pooled through random-effects meta-analysis. Results Twenty studies involving 3,468 patients were included. Inhaled antibiotics were associated with reduced number of patients with exacerbations (risk ratio, 0.85; 95% CI, 0.75-0.96), a slight reduction in exacerbation frequency (rate ratio [RR], 0.78; 95% CI, 0.68-0.91), a probable reduction in the frequency of severe exacerbations (RR, 0.48; 95% CI, 0.31-0.74), and a likely slight increase in time to first exacerbation (hazard ratio, 0.80; 95% CI, 0.68-0.94). Inhaled antibiotics likely lead to a slight increase in the Quality of Life Questionnaire-Bronchiectasis respiratory symptom score (mean difference, 2.51; 95% CI, 0.44-4.31) and may reduce scores on the St. George Respiratory Questionnaire (mean difference, –3.13; 95% CI, –5.93 to –0.32). Bacterial load consistently was reduced, but FEV1 was not changed with treatment. Evidence suggests little to no difference in adverse effects between groups (OR, 0.99; 95% CI, 0.75-1.30). Antibiotic-resistant organisms likely were increased by treatment. Interpretation In this systematic review and meta-analysis, inhaled antibiotics resulted in a slight reduction in exacerbations, a probable reduction in severe exacerbations, and a likely slight improvement in symptoms and quality of life in adults with bronchiectasis. Trial Registry International Prospective Register of Systematic Reviews; No.: CRD42023384694; URL: https://www.crd.york.ac.uk/prospero/.

Chronic infection with bacteria is a key component of the so-called vicious vortex of bronchiectasis.The most common organisms causing chronic infection in patients with bronchiectasis are Pseudomonas aeruginosa and Haemophilus influenzae, with Streptococcus pneumoniae, Staphylococcus aureus, Moraxella catarrhalis, and other enteric gram-negative organisms also being isolated frequently from sputum and BAL samples in these patients. 1Airway infection leads to chronic inflammation and impaired mucociliary clearance.Patients who are infected chronically therefore are at higher risk of recurrent exacerbations, and those infected with P aeruginosa are at particularly high risk.Studies suggest the presence of P aeruginosa is associated with an increase in exacerbations, a sevenfold increased risk of hospitalization, and threefold increased risk of mortality. 2,3acerbations are associated independently with impaired quality of life and mortality. 4Therefore, reducing the number of exacerbations is the cornerstone of long-term disease management.6][7] The use of inhaled antibiotics is an alternative that provides consistent deposition of high antibiotic concentrations directly to the site of infection with a lower risk of toxicity, systemic adverse events, and bacterial resistance. 8,9They have been part of the standard of care for patients with cystic fibrosis (CF) and have been in use for > 40 years in that patient population. 10,11e role of inhaled antibiotics in bronchiectasis unrelated to CF is less clear.Inhaled antibiotics currently are used in non-CF bronchiectasis management under distinct conditions: acute treatment for exacerbations, targeted eradication of P aeruginosa, and long-term maintenance therapy. 12The European Respiratory Society (ERS) guidelines in 2017 made a conditional recommendation to offer inhaled antibiotics to patients with P aeruginosa infection with $ 3 exacerbations/y, while recommending oral antibiotic prophylaxis with a macrolide such as azithromycin for patients without P aeruginosa infection. 12Subsequent to the ERS guidelines, a series of large phase 3 studies have increased the evidence base substantially for inhaled antibiotics in patients with bronchiectasis.A systematic review and meta-analysis conducted in 2019 including the results of the large RESPIRE and ORBIT trials concluded that inhaled antibiotics achieve a small but significant decrease in exacerbations compared with placebo without improvements in symptoms or quality of life. 13Subsequent publications have challenged this, suggesting an improvement in symptoms (cough and sputum production) when bacterial load is reduced with inhaled antibiotics. 14e inconsistent results achieved in individual trials leave a series of unanswered questions for clinicians regarding inhaled antibiotics, including the magnitude of potential benefits on exacerbations, whether patients should expect improvements in symptoms and quality of life with inhaled antibiotics, and whether benefits are limited only to patients with P aeruginosa infection or also extend to infection with other organisms.To address these questions, we performed an updated systematic review and metaanalysis of inhaled antibiotic use in adults with bronchiectasis.

Search Strategy and Selection Criteria
We report an update of the previously conducted meta-analysis published in 2019. 13The previous study searched relevant dates from inception through January 2019.To update the search, two investigators searched PubMed/MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from January 21, 2019, through December 13, 2022, for randomized controlled trials on long-term use of inhaled antibiotics in adult patients with bronchiectasis and chronic respiratory infections.For this review, the recently updated Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used. 15No language restrictions were applied.
Studies were considered eligible for review if they included adult patients (aged $ 18 years) with CT scan-confirmed bronchiectasis, used inhaled antibiotics as a treatment for stable patients (defined by the absence of exacerbation at baseline), had a duration of at least 4 weeks, and measured at least one of the prespecified clinical outcomes.The intervention group included any antibiotic class given through inhalation.The control group could be those receiving inhaled placebo (eg, saline solution) or no therapy.
We excluded trials that included patients with bronchiectasis resulting from CF, enrolled patients younger than 18 years, and administered treatment exclusively during an acute exacerbation of bronchiectasis.We also excluded nonrandomized trials and observational studies.The search criteria were applied in two stages.First, clearly ineligible studies were excluded based on abstract review only.Second, full manuscript review was used to determine final eligibility.
Unpublished work was identified by searching for the 2019 through 2022 abstract books of the largest respiratory medicine conferences, the American Thoracic Society conference and the ERS conference.Studies were included for review if they complied with the aforementioned inclusion criteria.Additionally, we searched the ClinicalTrials.govregistry using the term bronchiectasis as a query.To supplement these searches, the reference lists of relevant publications, previous meta-analyses, and guidelines were reviewed.
Two investigators (R. C. and H. C.) independently performed the study selection, reviewing all the citations and abstracts identified to assess which articles would be included.Disagreements were resolved by consensus discussion.If an agreement was not reached, a third investigator (J.D. C.) was available to review the article.We assessed risk-of-bias using the Cochrane risk-of-bias tool, RoB 2, as per Cochrane suggestions on updated meta-analyses.

Outcomes
End points were prespecified based on the previous meta-analysis and expert consensus on outcomes selected as important or critical in the European bronchiectasis guidelines. 12The primary outcome was the frequency of exacerbations.Additional selected outcomes included time to first exacerbation, proportion of patients with at least one exacerbation, frequency of severe exacerbations, quality of life (measured with the quality-of-life bronchiectasis questionnaire or the St. George Respiratory Questionnaire), lung function (measured as change in FEV 1 % predicted), sputum bacterial load (measured as change in colony-forming units/g, 24-h sputum volume), and percentage of sputum cultures with negative results. 16,17Adherence and mortality also were evaluated.Outcome data selection was based on values reported at the end of the intervention.
Safety end points were assessed by collecting data on the number of patients with treatment-emergent adverse events (TEAEs), the number of patients with adverse events that led to discontinuation, treatment-emergent serious adverse events, and the number of patients with bronchospasm as an adverse event of special interest.Bacterial resistance in sputum, defined as the proportion of bacterial isolates with a minimum inhibitory concentration of more than the resistance threshold, was also collected.
Planned subgroup analyses included antibiotic agent (aminoglycosides, fluoroquinolones, b-lactams, and polymyxins) and baseline infection status (populations limited exclusively to patients infected with P aeruginosa vs populations with mixed pathogens or no prespecified pathogen selection).

Data Analysis
Two authors (R. C. and H. C.) extracted end points of interest in a masked fashion.Data from each study were tabulated using a predesigned spreadsheet before inclusion in the analysis.For categorical binary outcomes, data with the number of participants with each outcome event were assessed in both the intervention and the placebo groups.Wherever possible, the intention-to-treat population was used as the denominator.For continuous outcomes, sample size, mean, SD, SE, or median (interquartile range) were extracted.If the mean relative change from baseline for each group and the SD or SE were reported, those data also were extracted.If not present, we calculated the mean difference and the 95% CIs for estimated pooled treatment effect, according to the recommended methods from the Cochrane Collaboration. 18If continuous outcomes were reported using different units or scales, a standardized mean difference and 95% CIs were calculated.For time-to-event outcomes, data were obtained from Cox proportional hazards model estimates when the log hazard ratio (HR) and its SE were provided by the study authors.Raw unadjusted data were sought wherever feasible.However, if the only available data were from adjusted models, these were pooled for analysis.For effect estimates, we obtained the number of participants in each group, the magnitude of the effect, and the respective CIs.
For the new studies, two authors (R. C. and H. C.) independently assessed the risk of bias by using Cochrane's collaboration revised risk-of-bias tool present in RevMan software version 5.4.1.A third author (C. S. H.) resolved any discordant data.Each potential source of bias was graded as low risk, unclear risk, or high risk of bias.
We expected high clinical heterogeneity because of evaluating different interventions (type of antibiotic used, difference in inhaler devices, dosage regimens) and differences in inclusion and exclusion criteria.Therefore, data were pooled using a random effects model.We performed analyses both with and without outlying studies as part of a sensitivity analysis. 18When data had been estimated, sensitivity analyses excluding such data were performed to check the influence chestjournal.org of any assumptions on the reported pooled effects.The P value from the c 2 test and the I 2 CIs are provided to describe heterogeneity.
We considered substantial heterogeneity when the I 2 was $ 50%. 18e evaluated certainty of evidence by using the Grading of Recommendations, Assessment, Development, and Evaluations method for the selected outcomes.Meta-analyses were carried out using RevMan version 5.4.1 software.The review protocol was registered prospectively with the International Prospective Register of Systematic Reviews (identifier, CRD42023384694).More detailed information on the study methods is provided in e-Appendix 1.

Results
The updated search identified 227 references.After the removal of 43 duplicates, 184 studies were screened.From these, 170 studies were deemed irrelevant based on title and abstract.One study was identified as an abstract and presentation at the ERS conference. 19We assessed 14 studies for eligibility.Ten studies were excluded.0][21][22][23][24][25][26][27][28][29][30][31][32][33] Of the four newly identified trials, two studies compared inhaled tobramycin with inhaled placebo, one using a conventional compressor nebulizer and the other using a vibrating mesh nebulizer. 27,33One study compared dry powder tobramycin with a placebo. 26he final study compared inhaled colistimethate sodium with placebo through an adaptive aerosol delivery mesh nebulizer. 19The primary end points of new studies were the number of exacerbations (Bronchiectasis and Tobramycin Solution Inhalation Therapy [BATTLE] trial), changes from baseline in P aeruginosa sputum density (i-BEST and Tobramycin in Bronchiectasis Colonized With Pseudmonas AeruginosaI [TORNASOL] studies), and exacerbation rate (PROMIS-I). 19,27,33 the previously identified 16 studies, eight assessed inhaled antibiotics in patients with P aeruginosa infection, and the remaining included patients infected with P aeruginosa, other pathogens, or a combination.Three new studies included only patients with P aeruginosa, and one study included other pathogens. 33  bronchiectasis populations of predominantly female patients with a mean age of 53 to 70 years.Study duration ranged from 6 weeks to 15 months, with treatment periods ranging from 4 weeks to 52 weeks.The 20 trials included reported data from 3,468 independent participants.[21][22][23][24][25][26][27][28][29][30][31][32][33] Outcomes of Included Studies Exacerbations: Trials assessed reported multiple exacerbation end points, expressing them as frequency of exacerbations, frequency of severe exacerbations, time to first exacerbation, and proportion of patients with at least one exacerbation.4][26][27][28][29][31][32][33][34] In the intervention group, 714 of 1,823 patients (39.1%) reported at least one exacerbation compared with 522 of 1,237 patients (42.1%) in the control group.The pooled relative risk was 0.85 (95% CI, 0.76-0.96;P ¼ .006)with nonsubstantial heterogeneity (I 2 ¼ 40%) and no significant subgroup difference between classes of antibiotics (P ¼ .26).These data indicate that inhaled antibiotic treatment is associated with a significant reduction in the proportion of patients experiencing at least one exacerbation.

Symptoms and Quality of Life
Inhaled antibiotics were associated with a significant improvement in respiratory symptoms using the Quality of Life Questionnaire-Bronchiectasis in 11 trials (N ¼ 2,315), with a mean difference change from baseline of 2.37 points (95% CI, 0.44-4.31;P ¼ .04;I 2 ¼ 48%), which is lower than the minimal clinically important difference of 8 points. 16Only one study showed an average improvement of a > 8-point difference in the per-protocol population. 27r the St. George Respiratory Questionnaire, pooled analysis of 10 trials (N ¼ 1,338) showed a significant difference in favor of the intervention (mean difference, -3.13; 95% CI, -5.93 to -0.32; P ¼ .03),28,31 The average between-group different was lower than the minimal clinically important difference of 4 points.Subgroup analysis of inhaled colistin showed a mean difference of more than the 4-point minimal clinically important difference (-6.58; 95% CI, -12.11 to -1.05; P ¼ .002; 19,28utum volume assessed as 24-h sputum volume in milliliters was reported previously in three trials (N ¼ 540). 24,27,28The pooled mean difference was -4.63 mL/24 h (95% CI, -8.42 to -0.84; P ¼ .02;
Bacterial eradication from sputum, defined by the absence of the baseline pathogen on the end-oftreatment sputum sample, was increased significantly with inhaled antibiotic treatment (OR, 3.65; 95% CI, 2.02-6.58;P < .0001),with high heterogeneity (I 2 ¼ 75%; N ¼ 2,370).6][27][28][30][31][32][33] Study or Subgroup   The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
b Grading of Recommendations, Assessment, Development, and Evaluations Working Group grades of evidence: high certainty ¼ we are very confident that the true effect lies close to that of the estimate of the effect; moderate certainty ¼ we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different; low certainty ¼ our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect; very low certainty ¼ we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
The heterogeneity can be attributed to the AIR-BX trials.Explanation is provided in the text.P value for heterogeneity remains > .05.
Weight average of studies with high risk of bias is 42.4%, with the rest of the studies being low risk of bias.

Risk of Bias
We assessed the risk of bias using the Cochrane risk of bias tool, RoB 2. 35 A high risk of bias was reported in five studies included in the previous metaanalysis. 24,25,28,30,32Regarding the new studies, three showed a low risk or unclear risk of bias, 26,27,33 and one study was considered to show a high risk of bias (e-Table 3

Discussion
This updated systematic review and meta-analysis provides novel information about the safety and efficacy of inhaled antibiotics in patients with bronchiectasis, with a focus in long-term maintenance therapy, with all the studies except one 32 having a duration of > 3 mo.We show that inhaled antibiotics are associated with a significant reduction in pulmonary exacerbations, with a pooled estimate of a 21% reduction.A much larger effect was observed on severe exacerbations requiring hospitalization or IV antibiotics at 52%.No minimal clinically important difference is reported for exacerbation reduction in bronchiectasis and attempts to derive such values have been controversial in other fields such as COPD. 36Nevertheless, in other diseases reductions of > 20% are regarded as highly clinically relevant. 37We conclude that inhaled antibiotics are associated with a clinically relevant reduction in exacerbations in diverse populations.
A striking finding of our analysis was that despite frequent discussion of the inconsistent results between inhaled antibiotic trials, 38,39 the results for exacerbations showed minimal heterogeneity and were remarkably consistent despite multiple differences in design, patient population, duration, and the antibiotic used.After exclusion of the AIR-BX studies, a set of studies that were notably different because they used no enrichment for patients with frequent exacerbations, no requirement for chronic infection at baseline, and a short follow-up duration, no significant heterogeneity in results between studies was found. 29Our analysis suggests that the true treatment effect lies somewhere between a 16% and 35% reduction in exacerbations.The inconsistent results of various trials simply may reflect that individual studies are powered frequently on the basis of much larger effects.For example, we found that inhaled antibiotics prolonged time to first exacerbation by 20%, but the RESPIRE trials were powered on a median increase of 67%. 40Therefore, although the frequently cited heterogeneity of the disease may be part of the explanation for the failure to achieve two replicatepositive randomized clinical trials in bronchiectasis for inhaled antibiotics, a failure to power trials properly for an average treatment effect of approximately 20% reduction in exacerbation frequency also may be a factor.

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A key novel finding of our analysis is that inhaled antibiotics significantly improve symptoms and quality of life, contradicting the results of the previous metaanalysis and some of the large phase 3 trials.We observed small but significant improvements in both the Quality of Life Questionnaire-Bronchiectasis and St. George Respiratory Questionnaire scores.The consistency in these results between two tools applied in different trials makes it more likely that these estimates are true reflections of the underlying treatment effect.Although neither difference is greater than the minimum clinically important difference on average, it is likely that some patients will experience a clinically meaningful change in symptoms.A post hoc analysis of the ORBIT trials identified a significantly higher number of patients experiencing an 8-point improvement in the Quality of Life Questionnaire-Bronchiectasis in the treatment vs the placebo group. 41A recent study found that patients experiencing a symptom improvement are not necessarily the same patients who experience a reduction in exacerbations. 42A high degree of heterogeneity in symptoms responses was found between studies, and further research is needed to understand why some populations experience a large symptom improvement and many do not.Patients are more likely to experience a symptom improvement if they show symptoms including cough and sputum production, because antibiotics primarily improve these symptoms. 14In support of this, we found that inhaled antibiotics reduce sputum volume.The magnitude of the differences observed in our analysis suggest that inhaled antibiotics will not be used primarily to reduce symptoms, but that patients being prescribed inhaled antibiotics to reduce exacerbations can be told that some patients also will experience a significant improvement in symptoms.
Safety of inhaled antibiotics is a key consideration, and in this regard, our results are reassuring.Adverse events were not increased significantly.Bronchospasm, which is a concern with inhaled antibiotics, also was not increased significantly except for with aminoglycosides.Withdrawals were more likely with aminoglycosides and aztreonam.Our data suggest that aminoglycosides are more likely to cause bronchospasm and discontinuation of treatment than other antibiotic classes.
An important subanalysis of our data suggested that the magnitude of benefits observed in populations including both P aeruginosa and non-P aeruginosa infections are comparable, and this is consistent with subgroup analysis data from mixed studies such as the RESPIRE trial, where no differences in response were observed between the groups. 20,21Current ERS guidelines suggest choosing inhaled antibiotics for P aeruginosa infections and oral antibiotics for non-P aeruginosa infections.Since 2017, macrolides have been shown to have efficacy in reducing exacerbations in patients infected with P aeruginosa, albeit in smaller numbers than have been studied in the inhaled antibiotic trials. 7Our data suggest that both macrolides and inhaled antibiotics are effective in both populations, and the choice of treatment may come down to the balance of risks and benefits of each drug for the individual patient, rather than the baseline pathogen.

Interpretation
In summary, this updated systematic review and metaanalysis offers a number of important observations, including a clinically relevant reduction in exacerbations and severe exacerbations with inhaled antibiotics, significant improvements in symptoms and quality of life, and reassuring safety and efficacy across the spectrum of respiratory pathogens.

Figure 1 -
Figure 1 -Preferred Reporting Items for Systematic Reviews and Meta-Analyses study flow diagram.

Figure 3 -
Figure3 -A, B, Forest plots showing of quality of life and symptom scales according to the Quality of Life Questionnaire-Bronchiectasis (QOL-B) (A) and the St. George Respiratory Questionnaire (SGRQ) (B).A negative score has been shown as a reduction in symptoms for ease of interpretation.In the original scales, a reduction in the scale indicates an improvement in symptoms with the SGRQ, but a worsening with the QOL-B.The weight of each study is the percentage of its contribution to the overall effect estimate.Weights of individual studies might not add up to the subtotal or overall weights because of rounding.Risk of bias is represented as low (þ), unclear (?), or high (-).df ¼ degrees of freedom; IV ¼ inverse variance; M-H ¼ Mantel-Haenszel.

Figure 5 -
Figure5 -A, B, Forest plots showing treatment-emergent adverse effects leading to discontinuation (A) and bronchospasm events (B).The weight of each study is the percentage of its contribution to the overall effect estimate.Weights of individual studies might not add up to the subtotal or overall weights because of rounding.Risk of bias is represented as low (þ), unclear (?), or high (-).Includes safety population.df ¼ degrees of freedom; IV ¼ inverse variance; M-H ¼ Mantel-Haenszel.

k
Concern in patient and personnel masking and incomplete outcome data.l Nonoverlapping CI; studies of low risk of bias with opposite results; P < .05for heterogeneity.m Wide CI overlapping with the minimal clinical difference of 4 points.n Assymetrical funnel plot, probably exacerbating effects.o CI includes benefit and harm.76 Original Research [ 1 6 6 # 1 C H E S T J U L Y 2 0 2 4 ] Subgroup Analysis of Studies with P aeruginosa and Other Bacterial Pathogens

Previous studies Identification Screening Included Identification of new studies via databases and registers
Most studies included

TABLE 1 ]
Characteristics of the Included Studies

TABLE 1 ]
(Continued)Data are No. (%) or mean AE SD, unless otherwise specified.6MWT ¼ 6-min walk test; BHQ ¼ Bronchiectasis Health Questionnaire; CFU ¼ colony-forming units; CMS ¼ colistimethate sodium; DPI ¼ dry powder for inhalation; IQR ¼ interquartile range; ITT ¼ intention-to-treat; LCQ ¼ Leicester Cough Questionnaire; LRTI-VAS ¼ lower respiratory tract infections visual analog scale; MIC ¼ minimum inhibitory concentration; NTM ¼ nontuberculous mycobacterial infection; QOL ¼ quality of life; QOL-B ¼ Quality of Life Questionnaire-Bronchiectasis; PP ¼ per protocol; PSSS ¼ pulmonary symptom severity score; RSS ¼ respiratory symptoms scale; SEM ¼ standard error of the mean; SGRQ ¼ St. George Respiratory Questionnaire; TIP ¼ tobramycin inhalation powder; TIS ¼ tobramycin inhalation solution.a 280 mg group vs 560 mg group vs placebo group.b Trials not reported in the previous meta-analysis.The RESPIRE-1 and RESPIRE-2 trials underwent assessment as distinct studies for the 14-d and 28-d cohorts; however, a pooled placebo group was used as a comparator.

46 [0.10, 2.12]
Figure2 -A, B, Forest plots showing frequency of exacerbations (A) and frequency of severe exacerbations (B).The weight of each study is the percentage of its contribution to the overall effect estimate.Weights of individual studies might not add up to the subtotal or overall weights because of rounding.Risk of bias is represented as low (þ), unclear (?), or high (-).df ¼ degrees of freedom; IV ¼ inverse variance.

44 [-6.79, 1.91]
Figure4-Forest plot showing isolated bacteria with a minimum inhibitory concentration of more than the resistant breakpoint at the end of treatment.The weight of each study is the percentage of its contribution to the overall effect estimate.Weights of individual studies might not add up to the subtotal or overall weights because of rounding.Risk of bias is represented as low (þ), unclear (?), or high (-).df ¼ degrees of freedom; IV ¼ inverse variance.

TABLE 2 ]
Key Findings of a Meta-Analysis of Inhaled Antibiotics for the Treatment of Adult Patients With Bronchiectasis HR ¼ hazard ratio; MD ¼ mean difference; MIC ¼ minimum inhibitory concentration; NA ¼ not applicable; NaN ¼ not a number; QOL-B ¼ Quality of Life Questionnaire-Bronchiectasis; RCT ¼ randomized controlled trial; RR ¼ rate ratio; RSS ¼ respiratory symptoms scale; SGRQ ¼ St. George Respiratory Questionnaire; TEAE ¼ treatment-emergent adverse event. a