Inhaled antibiotics and non-cystic fibrosis bronchiectasis: Trying to solve the puzzle

Abstract

Bronchiectasis is a chronic airway disease with recurrent exacerbations and hospitalisations. No inhaled antibiotic has shown consistently beneficial effects in trials. This review analyses the evidence on inhaled antibiotics in non-cystic fibrosis bronchiectasis (NCFB), identifies patient traits for their use, and highlights research gaps. A PubMed search for “Inhaled antibiotics AND bronchiectasis” identified five inhaled antibiotics studied in randomised controlled trials (RCTs): aztreonam, tobramycin, gentamycin, ciprofloxacin, and colistin. Inhaled antibiotics reduced exacerbation frequency, sputum bacterial density, and increased bacterial eradication but did not improve lung function. They also increased antimicrobial resistance, with aztreonam and aminoglycosides having higher discontinuation rates due to side effects. Increased sputum bacterial density (>10⁷ colony forming units/g), increased exacerbation frequency (≥4) at baseline, and increased sputum volume and/or purulence at baseline are some of identifiable traits associated with benefit from inhaled antibiotics. Inhaled antibiotics may aid in eradicating Pseudomonas aeruginosa after first isolation in NCFB, but their role in acute exacerbations requires further research. There are no direct RCTs comparing different delivery systems, antibiotics, and regimens.

INTRODUCTION

Bronchiectasis is a chronic airway disease marked by infection, inflammation, and irreversible airway damage.[1] Its pathophysiology follows the “vicious cycle model,” where bacterial colonisation, especially with Pseudomonas aeruginosa, leads to frequent exacerbations, lung function decline, and poor outcomes [Figure 1].[2,3] Chronic airway infection is a key treatable trait. While systemic antibiotics improve outcomes, their effectiveness is limited by low lung concentrations, systemic toxicity, and resistance. Inhaled antibiotics offer high lung concentrations with minimal systemic effects and lower resistance risk.[4] Though none of inhaled antibiotics are licensed for non-CF bronchiectasis, ERS (2017) and BTS (2019) guidelines recommend their use. This review analyses existing evidence, identifies patient traits suited for inhaled antibiotics, and highlights research gaps.

Figure 1.

Cole’s Vicious circle hypothesis of bronchiectasis

Search strategy and selection criteria

The PUBMED database was searched using the search term “Inhaled antibiotics AND bronchiectasis” without any time limitation. The search yielded 441 articles. The search results were supplemented by hand-picked articles from google search and reviewing the reference lists of the publications, meta-analyses, and guidelines. Only randomised controlled trials (RCTs) and articles published in English language were taken into consideration for this review. Articles on cystic fibrosis (CF), non-tuberculosis mycobacteria (NTM) bronchiectasis, and allergic bronchopulmonary aspergillosis (ABPA) were excluded. Ethical committee approval was not necessary since this is a review of already published studies.

Pharmacokinetic and pharmacodynamic rationale of inhaled antibiotics

The efficacy of an antibiotic in treating lung infection is determined by the concentration achieved in the epithelial lining fluid (ELF) and the pulmonary penetration ratio (ELF concentration divided by plasma concentration). Systemic administration of colistin and tobramycin does not achieve adequate Cmax/MIC (or) AUC/MIC ratios, where Cmax is the concentration achieved in the reference compartment, MIC is the minimum inhibitory concentration, which is the lowest antibiotic concentration that inhibits bacterial growth in the inoculum, and AUC is the area under the curve. This becomes very important in MDR (multi-drug-resistant) and XDR (extremely drug-resistant) organisms like Pseudomonas and Acinetobacter. Inhaled antibiotics offer the advantage of achieving higher ELF concentrations without systemic adverse effects.[5]

Stable non-cystic fibrosis bronchiectasis

Aztreonam

Aztreonam lysine for inhalation solution (AZLI) was studied in AIR-BX1 and AIR-BX2 trials [Table 1]. Intravenous formulations of aztreonam contain arginine, which can cause airway inflammation after long-term therapy, thereby making it inappropriate for inhalational usage. The dosing regimen used was 75 mg thrice daily in 4 weeks on/off cycles for 6 months via a vibrating mesh nebuliser (VMN). AZLI reduced sputum bacterial density and increased adverse effects and discontinuation rates with no beneficial effect on exacerbations or quality of life scores. The negative results of AIR-BX1 and AIR-BX2 trials are in contrast with the beneficial effects of aztreonam seen in cystic fibrosis patients. Usage of the same doses of aztreonam in NCFB studies as in CF studies, differences in airway clearance techniques between CF and NCFB, differences in tolerance to inhaled antibiotics between CF and NCFB patients, stratification of baseline cohorts based only on lung function in NCFB studies, and higher incidence of COPD and other comorbidities in NCFB patients, especially in elderly, are some of the reasons hypothesised for the lack of beneficial effects in AIR-BX trials.[6]

Table 1.

Studies of inhaled aztreonam in non-CF bronchiectasis patients

Study	Population	Intervention	Outcomes	Adverse events*
AIR-BX1 Barker et al. (2014)[6]	N=266 Age ≥18 years (+) Sputum culture positive for GNB	AZLI 75 mg thrice daily 4 weeks on/off for 3 cycles vs placebo (Follow up till 196 days) using Altera nebuliser (VMN)	Primary outcome Change in QOL-B-RSS at 4 weeks: No difference HR 0.8 (CI -3.1 to 4.7), p: 0.68 Other outcomes a. Change in QOL-B-RSS at 12 weeks: No difference b. TTFE at 16 weeks: No difference c. Sputum CFU density: Decreased in AZLI group at the end of week 4 and week 12	Increased compared to placebo Treatment related adverse events: 40%, Adverse events leading to aztreonam discontinuation: 22%, Dyspnea: 55%, Cough: 52%, Increased sputum: 47%, Fatigue: 42%, Pyrexia: 24%, Headache: 16%, Wheezing: 16%, Non-cardiac chest pain: 15%, Chills: 13%
AIR-BX2 Barker et al. (2014)[6]	N=274 Age ≥18 years (+) Sputum culture positive for GNB	AZLI 75 mg thrice daily 4 weeks on/off for 3 cycles vs placebo (Follow up till 196 days) using Altera nebuliser (VMN)	Primary outcome Change in QOL-B-RSS at 4 weeks: Statistically significant but no clinically significant difference HR 4.6 (CI 1.1 to 8.2), p: 0.011 Other outcomes a. Change in QOL-B-RSS at 12 weeks: No difference b. TTFE till 16 weeks: No difference c. Sputum CFU density: Decreased in AZLI group at the end of week 4 and week 12	Increased compared to placebo Treatment related adverse events: 33%, adverse events leading to discontinuation: 7% Cough: 49%, Dyspnea: 37%, Increased sputum: 44%, Fatigue: 19%, Pyrexia: 22%, Headache: 13%, Wheezing: 13%, non-cardiac chest pain: 7%, chills: 7%

AZLI: Aztreonam lysine for inhalation solution, GNB: Gram negative bacilli, QOL-B-RSS: Quality of life-bronchiectasis-Respiratory symptom scale, HR: Hazard ratio, TTFE: Time to first exacerbation, VBN: Vibrating mesh nebuliser, CI: 95% confidence interval. MCID (Minimum clinically important difference) for QOL-B-RSS is 8, Beta-2 agonist inhalation was given before AZLI in both trials, *Adverse events mentioned are for the study group

Tobramycin

Inhaled Tobramycin has been studied in both dried powder (TIP/Tobramycin inhalation powder) and nebulised forms (TIS/Tobramycin inhalation solution) in NCFB (non-cystic fibrosis bronchiectasis) patients [Table 2]. Phase 2 trials conducted by Barker et al. (n = 78) and Couch et al. (n = 74) using twice daily TIS for 4 weeks on NCFB patients with pseudomonas colonisation showed reduction in sputum bacterial density compared to placebo.[7,8] Scheinberg et al.[9] showed (n = 41) twice daily TIS in 14 days on/off cycles for 3 cycles increased pseudomonas eradication rates and improved St George Respiratory questionnaire (SGRQ) scores. Drobnic et al.[10] (n = 30) showed twice daily TIS reduced the number and days of hospital admissions and sputum bacterial density with no other clinical benefits. Loebinger et al.[11] (iBEST trial) used 84 mg once daily, 140 mg once daily, and 224 mg twice daily doses of TIP in continuous and intermittent (28 days on/off cycles) regimens for 16 weeks in NCFB patients (n = 107) with pseudomonas colonisation and two or more exacerbations in the previous year. TIP decreased sputum bacterial density and increased MIC values and discontinuation rates (8.8%) with no reduction in exacerbations or quality of life scores. Continuous and higher dosing regimens showed better results compared to intermittent and lower dosing regimens. Terpstra et al.[12] conducted a phase 3 trial (BATTLE study) on non-CF bronchiectasis patients (n = 58) with sputum bacterial colonisation using Tobramycin solution (TIS) 300 mg once daily for 52 weeks and found no significant benefit. Guan et al.[13] (TORNASOL study) (n = 357) showed TIS 300 mg twice daily in 28 days on/off cycle for 16 weeks reduced sputum bacterial density, sputum volume, and purulence and increased quality of life and MIC values in bronchiectasis patients with pseudomonas colonisation and at least one exacerbation in previous 12 months. However, there was no difference in frequency of exacerbations, lung functions, or adverse events compared to placebo, though discontinuation rates (6.2%) were higher with tobramycin. A meta-analysis was conducted on inhaled tobramycin in non-CF bronchiectasis patients with chronic pseudomonas aeruginosa infection. Inhaled tobramycin reduced sputum bacterial density, increased sputum bacterial eradication, reduced exacerbations requiring hospitalisations, and increased attrition rates due to respiratory adverse effects. However, there was no increase in the emergence of antibiotic resistance and no improvement in lung functions.[14] Several limitations exist within the studies reviewed. Many trials had small sample sizes, reducing statistical power. Further, variability in dosing regimens and treatment durations makes cross-study comparisons challenging. The negative results of BATTLE study may be attributed to an underpowered study design, the use of once-daily dosing, and a significant placebo effect. Key limitations of TORNASOL study include its predominantly Chinese cohort compared to the primarily Caucasian cohorts in other trials, limiting generalisability, higher mucolytic usage, and shorter study duration, which may have affected the results. Additionally, long-term data on resistance development and MIC increase remain lacking.

Table 2.

Studies of inhaled tobramycin in non-CF bronchiectasis patients

Study	Population	Intervention	Outcomes	Adverse events*
Barker et al. (2000)[8]	n=78, Age ≥18 years (+) Sputum culture positive for Pseudomonas aeruginosa	TIS 300 mg twice daily vs placebo twice daily for 4 weeks via PARI LC Plus jet nebuliser	Primary outcome Sputum bacterial density at week 4: Decreased, 4.54 log10 CFU/g, P<0.01 Other outcomes a. Sputum bacterial density at week 6: Decreased b. Medical condition: No difference c. FEV1: No difference d. Bacterial eradication from sputum: Increased (13/37) e. Hospitalizations and exacerbations: No difference	Adverse events: 84% Respiratory adverse events: 70% Dyspnea: 32% Chest pain: 19% Wheezing: 16%
Couch et al. (2001)[7]	n=74, Age ≥18 years (+), Sputum culture positive for Pseudomonas aeruginosa	TIS 300 mg twice daily vs placebo using PARI LC Plus Jet nebuliser for 4 weeks	a. Sputum bacterial density: Decreased b. Lung function: No difference c. Physician assessment of general health status: Improved, TIS group 62% vs Placebo group 38%	Dyspnea, chest pain and wheezing more common in TIS group Withdrawal due to adverse events: 8%
Scheinberg et al. (2005)[9]	n=41, Age ≥18 years (+), Pseudomonas aeruginosa in sputum	TIS 300 mg twice daily vs placebo in 14 days on/off regimen for 3 cycles	a. Sputum bacterial eradication at 12 weeks: 22.2% b. SGRQ scores: Significant improvement, mean change -9.8, P<0.001	Cough: 43.9% Dyspnea: 34.1% Increased sputum: 29.3% Wheezing: 26.8% Fatigue: 26.8% Headache: 17.1% Treatment related discontinuation: 22%
Drobnic et al. (2005)[10]	n=30, Age ≥18 years (+) Sputum colonized with Pseudomonas aeruginosa (+) Exacerbations	TIS 300 mg twice daily vs placebo for 6 months using Jet nebuliser 1 month washout and crossover to alternate group for 6 months	a. Frequency of exacerbations: No difference b. Number of admissions: Decreased, p: 0.038 c. Days of admission: decreased, p: 0.047 d. FVC and FEV1: No difference e. SGRQ scores: No difference f. Sputum bacterial density: Decreased during treatment, p: 0.038	Bronchospasm leading to withdrawal :10% Dyspnea and wheezing: 3% Hemoptysis: 3% Tinnitus: 3%
iBEST Loebinger et al. (2021)[11]	n=107, Age ≥18 years, Sputum culture positive for Pseudomonas aeruginosa (+) ≥2 exacerbations in previous 12 months	TIP Cohort A: 84 mg once daily vs placebo Cohort B: 140 mg once daily vs placebo Cohort C: 224 mg twice daily vs placebo (via T-326 inhaler in continuous and 28 days on/off cycle regimens for 16 weeks)	Primary outcome Sputum bacterial density at day 29: Decreased, -2.5 log10CFU/ml for 84 mg, p: 0.0004, −2.8 log10CFU/ml for 140 mg, −3.8 log10CFU/ml for 224 mg P≤0.0001 (pooled value) Other outcomes a. Cohort C and daily regimen: Higher efficacy in reducing sputum bacterial density b. MIC: increased in both cyclical and continuous TIP regimens compared to placebo but no difference between them c. Exacerbation frequency: No difference d. QOL-B score: No difference	Treatment emergent adverse events: 86% Discontinuation rates higher: Combined: 8.8% Cohort A: 14.7% Cohort B: 16.7% Cohort C: 37.8% Cough 18.7% Dyspnea 17.8%
BATTLE Terpstra et al. (2022)[12]	n=58 Age ≥18 years, Sputum culture positive for GNB or staphylococcus aureus	TIS 300 mg once daily vs placebo (0.9% saline) for 52 weeks via InnoSpire Deluxe compressor	Primary outcome Frequency of exacerbations: No difference, RR 0.74 (0.49-1.14), p: 0.15 Other outcomes a. TTFE: No difference b. Lung function: No difference c. QOL-B-RSS: No difference d. LRTI-VAS: Improved e. Leicester cough score: Improved	Cough: 26.9% Dyspnea: 11.5% Headache/dizziness: 7.7% Hoarseness: 7.7% Renal impairment: 7.7% Tinnitus: 3.8% Respiratory symptoms: 8.8% Bad taste: 3.8%
Tornasol Guan et al. (2023)[13]	n=357 Age ≥18 years (+) Sputum culture positive for pseudomonas aeruginosa (+) ≥1 exacerbation in previous 2 years	TIS 300 mg twice daily vs normal saline via vibrating mesh nebuliser in 28 days on/off cycle for 16 weeks	Primary outcomes a. Sputum pseudomonas aeruginosa density after 29 days: Decreased, Mean difference: 1.74 log10 CFU/g (CI 1.12-2.35) P<0.001 b. Change in QOL-B-RSS at 29 days: Increased, Mean difference: 7.91 (CI 5.72-10.11), P<0.001 Other outcomes a. Sputum pseudomonas aeruginosa density after 85 days: Decreased b. Change in QOL-B-RSS at day 85: Increased (statistically) c. Sputum purulence at day 57 and day 85: Decreased d. Sputum volume at day 57 and day 85: Decreased e. Exacerbation frequency: No difference f. FEV1: No difference g. MIC at day 29: Increased	Adverse events: 81.5% Trial discontinuation due to adverse events: 6.2% Hemoptysis: 20.8% Chest discomfort: 9.6% URTI: 8.4% Wheezing: 5.6% Cough: 11.8% Chest pain: 7.3% Fever: 6.2% Blurred vision and dizziness: 0.6% Renal impairment: 0.6%

(i.v): Intravenous, TIS: Tobramycin inhalation solution, TIP: Tobramycin inhalation powder, CFU: colony forming unit, FEV1: Forced expiratory volume in 1 second, SGRQ: St George Respiratory Questionnaire, FVC: Forced vital capacity, MIC: Minimum inhibitory concentration, QOL-B-RSS: Quality of life-Bronchiectasis-Respiratory symptom scale, LRTI-VAS: Lower respiratory tract infection-visual analog scale, MCID (Minimum clinically important difference) for QOL-B-RSS is 8, CI: 95% confidence interval, *Adverse events mentioned are for the study group

Gentamycin

Nebulised gentamycin was studied in 80 mg twice daily regimen [Table 3]. Murray et al.[15] studied nebulised gentamycin for 12 months in non-CF bronchiectasis patients (n = 65) with sputum bacterial colonisation and frequent exacerbations. They found nebulised gentamycin increased sputum bacterial eradication with rates of 92.8% with non-pseudomonas organisms and 30.8% with Pseudomonas aeruginosa. Other findings included reduction in sputum purulence, an increase in exercise capacity, improvement in quality-of-life scores, and reduction in frequency of exacerbations, but there was no improvement in lung functions. Twiss et al.[16] studied nebulised gentamycin in bronchiectasis patients in the 5 to 15 years age group with Hemophilus influenza colonisation (n = 15) in a cross-over study. They found nebulised gentamycin reduced sputum bacterial density and improved bacterial clearance with no improvement in any clinical outcomes. Gentamycin trials had enrolled small sample size and had poor adherence rates during the study period affecting their outcome measures.

Table 3.

Studies of inhaled gentamycin in stable non-CF bronchiectasis patients

Study	Population	Intervention	Outcomes	Adverse events*
Murray et al. (2011)[15]	n=65, ≥2 exacerbations in the previous 12 months (+) Sputum culture positive	Nebulised gentamycin 80 mg diluted in normal saline twice daily using Porta-neb Ventstream nebuliser vs placebo nebulisation for 12 months	a. Sputum bacterial eradication at 12 months: Increased b. Eradication of Pseudomonas aeruginosa group: 30.8% c. Eradication of bacteria other than Pseudomonas: 92.8% d. Sputum purulence: Decreased at 6 months, 9 months and 12 months in Gentamycin group e. Lung function: No difference f. Exercise capacity at 12 months: Increased g. Quality of life scores: Improved h. Exacerbation frequency: Decreased	Bronchospasm: 21.9% (7/32 patients) Bronchospasm related treatment withdrawal: 28.5% (2/7) Unpleasant taste:11.1%
Twiss et al. (2022)[16]	n=15, Age: 5 to 15 years, Sputum culture positive	Nebulised Gentamycin 80 mg (2 ml) + 2 ml 0.9% saline twice daily vs Placebo Using LC PLUS nebuliser for 12 weeks followed by 6 weeks washout, then switched to alternate treatment group for 12 weeks, followed by 6 weeks washout	Primary outcomes a. FEV1 predicted: No difference, 56% vs 55%, p: 0.384 b. Exacerbations requiring admission: No difference, 1.1 vs 0, p: 0.123 c. Number of days in hospital for exacerbation: No difference, 19.3 vs 0, p: 0.120 Other outcomes a. FVC predicted: No difference b. FEF 25-75% predicted: Increased c. Oral antibiotics: Decreased d. Oral/intravenous antibiotics: No difference e. Symptom severity score: Decreased f. Sputum bacterial density: Decreased g. Sputum inflammatory markers (IL-1β, IL-8, TNF-α): Decreased	Not increased compared to placebo

FEV1: Forced expiratory volume in 1 second, FVC: Forced vital capacity, FEF: Forced expiratory flow. *Adverse events mentioned are for the study group. Beta -2 agonist inhaler was given prior to the study drug in patients reporting symptomatic bronchospasm

Ciprofloxacin

Inhaled ciprofloxacin has been studied in two formulations: DPI (dry powder inhalation) and liposomal form.[17] Liposomal formulation has a lung clearance half-life of 12 hours compared to 1 hour for the free form. Pulmaquin^TM or dual release formulation (DRCFI) has a mixture of Lipoquin^TM and free CFX Pulmaquin,^TM thereby leading to an initial rapid release followed by prolonged action.[18] The dosage tried for DPI CFX is 32.5 mg twice daily and that for DRCFI (liposomal ciprofloxacin) is (135 mg liposomal CFX + 54 mg free CFX) once daily in 14 days on/off cycles and 28 days on/off cycles regimens in phase 3 studies [Table 4].

Table 4.

Studies of inhaled ciprofloxacin in stable non-CF bronchiectasis patients

Study	Population	Intervention	Outcomes	Adverse effects*
Wilson et al. (2013)[17]	N=124, Age ≥ 18 years (+) ≥ 2 exacerbations in previous 12 months (+) Sputum culture positive	DPI CFX 32.5 mg twice daily vs placebo for 28 days	Primary outcome Sputum bacterial density after 28 days: Decreased, -3.62 log10 CFU/g (CI -9.78 to -5.02), P<0.001 Other outcomes a. Exacerbation frequency: No difference b. Lung function: No difference c. Eradication of bacteria from sputum: Increased d. MIC values: Increased	Not increased compared to placebo TE-AE: 68.3% Product taste abnormal: 13.3% Dysgeusia: 6.7% Exacerbation of bronchiectasis: 11.7% Headache: 6.7%
ORBIT-2 Serisier et al. (2013)[19]	N=42, Age ≥ 18 years (+) ≥ 2 exacerbations in 12 months (+) ciprofloxacin sensitive Pseudomonas aeruginosa infection	DRCFI (150 mg LC in 3 ml + 60 mg FC in 3 ml) once daily in 28 days on and 28 days off cycle for 24 weeks	Primary outcome Sputum bacterial density: Decreased, −4.2±3.7 log10 CFU/g, p: 0.002 Other outcomes a. TTFE: Increased (Per protocol Analysis) b. Exacerbation frequency: Decreased c. 6 MWT, SGRQ, lung functions: No difference	Not increased compared to placebo Product taste abnormal: 20% Nausea: 20% Headache: 5%
RESPIRE- 1 De Soyza et al. (2018)[20]	N=416, Age ≥ 18 years (+) ≥ 2 exacerbations in previous 12 months (+) Sputum culture positive	DPI CFX for 48 weeks 32.5 mg twice daily vs placebo in 14 days on/off cycles and 28 days on/off cycles	Primary outcomes TTFE till 48 weeks: Increased (14 days on/off regimen) 336 days vs 186 days, p: 0.0005 Exacerbation frequency: Decreased (14 days on/off regimen), IRR 0.61 (CI 0.40 to 0.91), p: 0.0061 Other outcomes a. Eradication of bacteria from sputum: Increased b. SGRQ scores: Improved c. MIC values: Increased	Not increased compared to placebo TE-AE: 82.4% Discontinuation rates due to TE-AE: 12.5% Dyspnea: 11.8%, Hemoptysis: 11.8%, Cough: 9.6%, Bronchospasm: 5.1%, Sputum increased: 4.4%, Nasopharyngitis: 11.8%, URTI: 6.6%, Headache: 10.3%, Fatigue: 8.8%
RESPIRE 2 Aksamit et al. (2018)[21]	N=521 Age ≥ 18 years (+) ≥ 2 exacerbations in previous 12 months (+) Sputum culture positive	DPI CFX for 48 weeks 32.5 mg twice daily vs placebo 14 days on/off cycle and 28 days on/off cycle	Primary outcomes a. TTFE till 48 weeks: No difference (14 days on/off regimen) HR: 0.87 (CI 0.62 to 1.21), p: 0.3965 b. 28 days on/off regimen: HR 0.71 (CI 0.39-1.27), p: 0.0511 c. Frequency of exacerbations: No difference	Not increased compared to placebo TE-AE: 64.9%, Discontinuation due to TE-AE: 5.7% Hemoptysis: 9.8%, cough: 4%, Bronchospasm: 4%, Dyspnea: 5.7%, Nasopharyngitis: 9.2%, URTI: 4.6%, Dysgeusia: 4.6%
ORBIT-3 Haworth et al. & Chalmers et al. (2019)[22,23]	N=278 Age ≥ 18 years (+) ≥ 2 exacerbations in previous 12 months (+) Sputum culture positive for Pseudomonas aeruginosa	DRCFI for 48 weeks (135 mg LC in 3 ml+54 mg FC in 3 ml) once daily 28 days on and 28 days off	Primary outcome TTFE till 48 weeks: No difference, 214 days vs 136 days, p: 0.97 Other outcomes a. Frequency of exacerbations: No difference b. QOL-B-RSS: Improved (during on period) c. FEV1: No difference	Not increased compared to placebo Adverse events related to drug: 43% Cough: 62%, Dyspnea: 57% Increased sputum: 45%, Fatigue: 39%, Pyrexia: 26%, Wheezing :38% Hemoptysis: 17%, Oropharyngeal pain: 7%, Bronchospasm: 1%
ORBIT-4 Haworth et al. & Chalmers et al. (2019)[22,23]	N=304 Age ≥ 18 years (+) ≥ 2 exacerbations in previous 12 months (+) Sputum culture positive for Pseudomonas aeruginosa	DRCFI for 48 weeks (135 mg LC in 3 ml+54 mg FC in 3 ml) once daily 28 days on and 28 days off	Primary outcome TTFE till 48 weeks: Increased, 230 days vs 158 days, p: 0.032 Other outcomes a. Frequency of exacerbations: Decreased b. QOL-B-RSS: Improved (during on period) c. Lung function: No difference	Not increased compared to placebo Adverse events related to drug: 28%, Cough: 67%, Dyspnea: 52%, Increased sputum: 48%, Wheezing: 41%, Fatigue: 34%, Pyrexia: 20%, Hemoptysis: 13%, Bronchospasm: 1%
Pooled analysis of ORBIT-3 and ORBIT-4: Haworth et al. & Chalmers et al. (2019)[22,23]			Primary outcome TTFE till 48 weeks: No difference, 222 days vs 157 days, p: 0.074 Other outcomes a. Frequency of exacerbations: Decreased b. QOL-B-RSS: Improved (during on period) c. FEV1: No difference	Not increased compared to placebo

DPI CFX: Ciprofloxacin dry powder for inhalation, DRCFI-Dual release ciprofloxacin for inhalation, LC-Liposomal ciprofloxacin, FC-Free ciprofloxacin, DPI CFX delivered using T-326 breath actuated inhaler (Novartis) using Pulmosphere technology, DRCFI delivered using Jet (PARL LC sprint) nebulizer, N: number of participants, CI: 95% Confidence interval, HR: Hazard ratio, IRR: Incidence rate ratio, 6 MWT: 6-minute walk distance testing, SGRQ: St George Respiratory Questionnaire, TTFE: Time to first exacerbation, QOL-B-RSS: Quality of life-bronchiectasis respiratory symptom scale, MIC: Minimum inhibitory concentration, URTI: Upper respiratory tract infection, TE-AE: Treatment emergent adverse events. *Adverse events mentioned are for the study group

Wilson et al.[17] conducted a study using DPI CFX on non-CF bronchiectasis patients (n = 124) with two or more exacerbations in the previous 12 months and found reduction in sputum bacterial density and an increase in MIC values with no other outcome benefit. Serisier et al.[19] conducted a phase 2 trial (ORBIT-2 study) using DRCFI in 28 days on/off cycle for 24 weeks on non-CF bronchiectasis patients (N = 42) with pseudomonas colonisation and two or more exacerbations in the previous 12 months. They found reduction in sputum bacterial density, an increase in time to first exacerbation, and reduction in exacerbation frequency with no improvement in lung function or SGRQ scores. De Soyza et al.[20] conducted a phase 3 trial (RESPIRE-1 study) using DPI CFX for 48 weeks on non-CF bronchiectasis patients (n = 416) with frequent exacerbations. They found an increase in time to first exacerbation, reduction in frequency of exacerbations, improvement in SGRQ scores, an increase in sputum bacterial eradication, and an increase in MIC values. A similar study (N = 521) conducted by Aksamit et al.[21] (RESPIRE-2 study) showed no benefit in any of the outcomes. The reasons hypothesised for discordant results between the two studies are selection bias due to lack of proper definition for exacerbations during recruitment and heterogeneity between the two trials. RESPIRE-2 trial patients at baseline were relatively younger and had poorer lung functions, more respiratory symptoms, and fewer exacerbations during the trial period. Also, RESPIRE-2 trial recruited more patients with COPD (28%) than RESPIRE-1 (16%) and patients of Eastern European and Asian ancestry. Haworth et al. conducted two phase 3 trials (ORBIT-3 study and ORBIT-4 study) using DRCFI on non-CF bronchiectasis patients with pseudomonas colonisation and frequent exacerbations. ORBIT-3 study showed no benefit, while ORBIT-4 study showed an increase in time to first exacerbation, reduction in frequency of exacerbations, and improvement in quality-of-life scores. The differences between the results of ORBIT-3 and ORBIT-4 trials could be due to heterogeneity in macrolide usage at baseline between the study group and placebo group, fewer exacerbations in the placebo group at baseline, and using TTFE (time to first exacerbation) as the primary outcome, which might not be a suitable outcome measure as compared to frequency of exacerbations. Pooled analysis from both studies showed reduction in frequency of exacerbations and improvement in quality-of-life scores with no improvement in lung functions or time to first exacerbation. The reduction in exacerbations during the treatment is more in those with more frequent exacerbations (four or more) at baseline, and the beneficial effects are seen irrespective of baseline macrolide usage.[20,22,23] A meta-analysis conducted by Lim et al.[24] showed inhaled ciprofloxacin increased time to first exacerbation, HR 0.74 (CI 0.63–0.86), p: 0.0001, reduced frequency of exacerbations, RR 0.73 (CI 0.61–0.86), p-0.0003, increased sputum bacterial eradication, RR 1.93 (CI 1.07–3.49), p: 0.005, and increased the emergence of antibacterial resistance, RR 1.84 (CI 1.41–2.39), P < 0.00001, with no improvement in lung functions. Another meta-analysis by Wang et al.[25] showed similar results and there was no difference in any of the outcomes between DPI CFX and DRCFI.

Colistin

Colistin has been tried in nebulised form using 1 million units twice daily dosing via a vibrating mesh nebuliser [Table 5]. A study by Haworth et al.[26] using nebulised colistin in bronchiectasis patients (N = 144) with pseudomonas colonisation found no benefit in prolonging time to first exacerbation. There was however reduction in sputum bacterial density and improvement in SGRQ scores. Two large phase 3 RCTs (PROMIS-I and PROMIS-II studies) using nebulised colistin for 12 months in non-cystic fibrosis bronchiectasis with Pseudomonas colonisation and two or more exacerbations in the previous 12 months showed contrasting results with PROMIS-I study showing favourable results in terms of reduction in exacerbation frequency, an increase in time to first exacerbation, and reduction in sputum bacterial density and PROMIS-II study showing no benefit in any of the outcome measures. The PROMIS-II study was conducted during the COVID-19 pandemic. This led to insufficient sample size due to premature termination and fewer exacerbations in the placebo group thereby increasing type-2 error. Meta-analysis of PROMIS-1 and pre-pandemic PROMIS-II data showed positive results, while the pandemic period data from PROMIS-II showed no benefit.[27]

Table 5.

Studies of inhaled colistin in stable non-CF bronchiectasis patients

Study	Population	Intervention	Outcomes	Adverse effects*
Haworth et al. (2014)[26]	n=144 Age ≥18 years (+) Sputum culture positive for Pseudomonas aeruginosa (+) one exacerbation within 21 days of enrolment	Nebulised colistin 1 million units (diluted in 1 ml 0.45 normal saline) twice daily vs placebo via I-Neb for 6 months	Primary outcome TTFE: No difference 165 days vs 111 days, p: 0.11 Other outcomes a.At an adherence ≥81%, TTFE: Increased, 168 days vs 103 days, p: 0.038 b.Sputum bacterial density at week 4 and week 12: Decreased c.SGRQ at week 26: Decreased d.FEV1: No difference	Not increased compared to placebo TE-AE: 64% Adverse events leading to withdrawal: 9.6% Bronchospasm 7%
PROMIS-I Haworth et al. (2024)[27]	n=377 Age ≥18 years (+) Sputum culture positive for Pseudomonas aeruginosa (+) ≥2 exacerbations in previous 12 months	Nebulised colistin 1 million units twice daily vs placebo via I-Neb for 12 months	Primary outcome Exacerbation rate: Decreased RR 0.61 (CI 0.46–0.82), p: 0.0010 Other outcomes a.TTFE: Increased b.SGRQ scores after 12 months: Improved c.Sputum bacterial density: Decreased d.Severe exacerbations: Decreased	Not increased compared to placebo TE-AE: 81% Study drug withdrawal due to TA-AE: 13% Cough: 12% Dyspnea: 13% Hemoptysis: 5% Sputum increase: 7%
PROMIS-II Haworth et al. (2024)[27]	n=287, Age ≥ 18 years (+) Sputum culture positive for Pseudomonas aeruginosa (+) ≥2 exacerbations in previous 12 months	Nebulised colistin 1 million units twice daily vs placebo via I-Neb for 12 months	Primary outcome Exacerbation rate: No difference, RR 1.00 (CI 0.75-1.35), p: 0.98 Other outcomes a.TTFE: No difference b.SGRQ scores after 12 months: No difference c.Sputum bacterial density: No difference d.Severe exacerbations: No difference	Not increased compared to placebo TA-AE: 81% Study drug withdrawal due to TA-AE: 11% Cough: 7% Dyspnea: 5% Hemoptysis: 6% Sputum increase: 2%

TTFE: Time to first exacerbation, SGRQ: St. George respiratory questionnaire, RR: Risk ratio, CI: 95% confidence interval, TE-AE; Treatment emergent adverse events, I-Neb is a type of vibrating mesh nebuliser. *Adverse events mentioned are for the study group

Patient-centred outcome

Aztreonam improved cough, sputum production, and quality of life in high bacterial load (>10⁷ CFU/g of sputum) patients as seen from post-hoc analysis of AIR-BX1 and AIR-BX2 trials.[28,29] Tobramycin and gentamycin improved quality of life, sputum characteristics, and symptoms.[7,8,9,10,11,12,13,15,16] Although ciprofloxacin showed improvement in quality of life and SGRQ scores in RCTs, this effect was not seen in meta-analyses.[24,25] Colistin showed significant SGRQ score improvements in PROMIS-I and PROMIS-II trials.[27] A meta-analysis by Cordeiro et al.[30] showed inhaled antibiotics reduced sputum volume and improved symptoms, but only colistin showed clinically significant improvement in SGRQ scores reaching a MCID (minimal clinically important difference) of 4. Lung function remained unaffected.

Possible reasons for discordant results between the RCTs

Discordant RCT results in inhaled antibiotics for NCFB stem from heterogeneity in study cohorts, treatment regimens, and outcome measures. Variations include bacterial species (Pseudomonas vs non-Pseudomonas), exacerbation definitions leading to selection bias, exacerbation frequencies at baseline, treatment schedules (cyclical vs continuous), delivery methods (DPI vs nebuliser), and cultural/geographical factors leading to reporting and/or recall bias and different primary outcome measures.[31] AIR-BX trials had around 40% patients with two exacerbations at baseline, while PROMIS I and PROMIS II trials had most of the patients with two or more exacerbations at baseline; most studies were done predominantly on Caucasian cohorts, while TORNASOL study was done on Chinese cohorts; ciprofloxacin trials (RESPIRE- 1 and RESPIRE-2, ORBIT-3 and ORBIT-4) and tobramycin trials (iBEST and TORNASOL) used intermittent treatment regimens, while gentamycin studies and colistin (PROMIS I and PROMIS II) studies used continuous treatment regimens. AIR-BX trials, BATTLE study, and gentamycin studies enrolled pseudomonas and non-pseudomonas colonised patients at baseline, while colistin studies (PROMIS I and PROMIS II) and ciprofloxacin studies (RESPIRE and ORBIT trials) enrolled predominantly pseudomonas colonised patients at baseline. Aztreonam trials (AIR-BX1 and AIR-BX2) used quality-of-life scores, and colistin studies (PROMIS-I and PROMIS-II) used frequency of exacerbations as their primary outcome measures [Tables 1-5].

Drug delivery systems: Which one to choose?

An EMBARC survey found most professionals preferred nebulisers (78.4%) over DPIs (5.2%) for inhaled antibiotics, with jet nebulisers preferred (51.1%) over VMN (vibrating mesh nebulisers) (27.8%) and ultrasonic nebulisers (8.9%). The choice was determined by medicine compatibility, ease of use and cleaning, compliance with generating standard particle size, cost, and availability.[32] A study by Davison et al.[33] showed DPIs had shorter administration time than nebulisers, women reported more side effects with nebulisers than men, 14.7% patients reported poor adherence with nebulisers, 77.7% reported side effects as the reason for discontinuing nebulisers, and most of them preferred to be switched to non-nebulised inhaled antibiotics. A network meta-analysis by Tejada et al.[34] found DPIs and nebulisers equally effective, with DPIs slightly improving quality-of-life scores and delaying exacerbations, but no difference in safety or microbial resistance. Table 6 summarises the various factors determining the choice between DPI and nebulisers.

Table 6.

Comparison of nebulisers and DPI (Dry powder inhalers) for inhaled antibiotics

	Nebulisers	DPI
Manufacturing and formulation	Easy	Difficult
Ease of use	Less	Better
Children and elderly	Suitable	Not-suitable
Portability	Difficult	Easy
Amount of drug delivered	Large	Small
Patient cooperation	Not needed	Needs specific breathing pattern
Inspiratory effort needed	Normal tidal breathing	Good inspiratory effort
Time needed to administer	Longer (Especially for jet nebulisers)	Shorter
Cleaning of devices	Needed and difficult (Especially for vibrating mesh and Jet nebulisers)	Not needed
Availability	Easy	Varies from place to place
Cost	Varies from place to place	Varies from place to place
Adherence	Poor	Good

Newer drug delivery systems

Newer drug delivery systems show improved aerosolisation and/or biofilm penetration. Liposomal formulations have a lipid bilayer which gets engulfed by alveolar macrophages, and the drug is released, which then penetrates the bacterial biofilm layer. This effect is expected to prolong the duration of action and reduce the emergence of bacterial resistance. Amikacin is the only drug approved in liposomal formulation for the treatment of MAC (Mycobacterium avium complex) infection not responding to conventional treatment. Pooled analysis of ORBIT-3 and ORBIT-4 trials showed liposomal ciprofloxacin is tolerated well but failed to show benefit in the primary outcome of time to first exacerbation and hence was not approved. Other newer inhaled antibiotic delivery systems like PMCylation, chitosan microparticles, and coformulation of inhaled antibiotics are yet to be studied in phase 3 trials, although pre-clinical studies have shown promising results.[4,35]

Continuous versus intermittent regimen

Intermittent dosing regimens aimed to reduce antibiotic resistance due to continuous antibiotic exposure but showed limited sustained benefits. ORBIT-3 and ORBIT-4 trials found improved QOL-B-RSS scores and reduced sputum bacterial density only during the “on period” with benefits lost in the “off period”.[22,23] Inhaled tobramycin studies showed continuous regimens were more effective in reducing sputum bacterial density, though MIC values increased in both continuous and cyclical regimens. Also, sputum bacterial density decreased during the “on period” returning to almost baseline during the “off period” in cyclical treatment regimen.[11,13] PROMIS-I and PROMIS-II trials showed inhaled colistin in continuous regimen for 12 months was tolerated well. Thus, continuous treatment regimens seem more effective than cyclical regimens.

Targetable traits for inhaled antibiotics

Patients with frequent exacerbations (≥4 per year), chronic bronchitis symptoms (increased sputum production and purulence), and high bacterial loads (>10⁷ CFU/g) may derive the greatest benefit from inhaled antibiotics in stable non-CF bronchiectasis. Retrospective studies and post-hoc analyses of RCTs (AIR-BX, ORBIT) suggest that these characteristics are associated with improved outcomes, including quality of life and potentially fewer exacerbations. Identifying and targeting this subgroup in future trials could help optimise the use of inhaled antibiotics in bronchiectasis management.[29,36]

Adverse effects of inhaled antibiotics

Aztreonam (AIR-BX1 and AIR-BX2) had adverse events in up to 40% of cases, with dyspnoea (up to 55%), cough (up to 52%), increased sputum (up to 47%), and pyrexia (up to 24%) being most common; discontinuation rates reached 22% [Table 1].[6] Tobramycin had similar discontinuation rates (22%), with common side effects including cough (up to 43%), dyspnoea (up to34%), haemoptysis (up to 21%), and wheezing (up to 27%).[7,8,9,10,11,12,13] [Table 2]. Gentamycin caused bronchospasm (up to 22%), unpleasant taste (11.1%), and high discontinuation (28.5%) [Table 3].[15,16] Ciprofloxacin was well tolerated, with adverse events like cough, dyspnoea, and wheezing similar to placebo; the discontinuation rates were 5.7–12.5% [Table 4].[20,21,22,24,25] Colistin showed good adherence with lower adverse event rates (cough 12%, dyspnoea 13%) [Table 5].[27] MIC values increased with long-term inhaled antibiotics but did not impact clinical outcomes as seen in ORBIT and RESPIRE trials due to high airway antibiotic concentrations. Systemic resistance was not observed, but long-term follow-up is needed to look for clinical and ethical implications.[22,36]

Choosing among the antibiotics

There are no RCTs comparing different inhaled antibiotics in NCFB. Meta-analyses on inhaled antibiotics in NCFB show they reduce exacerbation risk (NNT 59), increase sputum bacterial eradication (NNT 3), and raise antibiotic resistance (NNT 6). They do not significantly impact lung function, hospitalisations, quality of life, or mortality. Sub-group analysis showed only colistin led to clinically significant improvement in quality of life. Inhaled antibiotics reduce exacerbation frequency by 21% (RR 0.79) and severe exacerbations by 52% (RR 0.48) while increasing antibiotic resistance (RR 1.86) and adverse events, particularly with aztreonam (OR 2.13) and aminoglycosides (bronchospasm RR 2.99). Benefits are seen in both Pseudomonas and non-Pseudomonas colonised patients, with inhaled ciprofloxacin (RESPIRE-1 and RESPIRE-2 trials), tobramycin (BATTLE trial), and gentamycin (Murray et al.) showing efficacy in the latter sub-group as well.[15] To summarise, aztreonam offers no benefit and increases adverse events, aminoglycosides show good efficacy but with increased rates of bronchospasm, and colistin and ciprofloxacin demonstrate good efficacy and better tolerance with fewer side effects.[30,37] A comparative analysis of different inhaled antibiotics is summarised in Table 7, and a stepwise approach in stable bronchiectasis patients is shown in Figure 2.

Table 7.

Comparative analysis of inhaled antibiotics in non-cystic fibrosis bronchiectasis

Inhaled antibiotic	Reducing exacerbations	QOL /symptom improvement	Pseudomonas colonised patients benefit (Y/N)	Non-pseudomonas colonised patients benefit (Y/N)	Adverse events	Discontinuation rates	Inhaler device type used in RCTs	Availability in India	FDA-approved
Aztreonam	No	+	N	N	High	High	VMN	Yes (Injection form)	No
Tobramycin	Yes	+	Y	Y	High	High	Breath enhanced jet nebuliser, VMN, Breath actuated inhaler	Yes (Nebuliser form commercially available)	No
Gentamycin	Yes	+	Y	Y	High	High	VMN	Yes (Injection form)	No
Ciprofloxacin	Yes	+	Y	Y	Low	Low	Breath enhanced jet nebuliser, Breath actuated inhaler	No	No
Colistin	Yes	++	Y	N	Low	Low	Adaptive aerosol delivery VMN	Yes (Injection form)	No

QOL: Quality of life, +: statistically significant, ++: statistically and clinically significant, VMN: Vibrating mesh nebuliser, Y: Yes, N: No, NA: Not applicable due to non-availability in India

Figure 2.

Stepwise approach in stable bronchiectasis patients

Guidelines statements on inhaled antibiotics for stable bronchiectasis

The ERS (2017) (conditional recommendation) and BTS (2019) (Grade of recommendation B) guidelines recommend long-term inhaled antibiotics for pseudomonas (Preferred 1^st: colistin, 2^nd line/alternative: gentamicin) and non-pseudomonas (only as 2^nd line: gentamycin) colonised bronchiectasis patients with three or more exacerbations per year. These recommendations are based on limited evidence from a single colistin study, a small RCT on nebulised gentamicin, the AIR-BX trials on aztreonam, and the ORBIT-2 study on inhaled ciprofloxacin [Table 8].[6,15,19,26] Systemic macrolides remain the 1^st treatment for non-pseudomonas colonised patients, given strong evidence from the EMBRACE, BLESS, and BAT trials and relatively fewer pseudomonas patients in these studies.[38,39,40] Aztreonam was not recommended due to its lack of efficacy and increased adverse effects, while inhaled ciprofloxacin and tobramycin were excluded due to insufficient evidence at the time.[30,37] Since 2017, additional studies including iBEST, BATTLE, and TORNASOL trials on tobramycin, PROMIS-I and PROMIS-II trials on colistin, and RESPIRE and ORBIT trials on ciprofloxacin along with two meta-analyses have provided new insights. These findings may impact future guideline updates.

Table 8.

Comparison of ERS (2017) and BTS (2019) guidelines for inhaled antibiotics in bronchiectasis

Long-term antibiotics for stable bronchiectasis	ERS (2017)	BTS (2019)	Basis of recommendation
Indication	≥3 Exacerbations/year (conditional recommendation, moderate quality evidence)	≥3 Exacerbations/year (Grade of recommendation A)	Several well conducted RCTs and Meta-analyses of oral and/or inhaled antibiotics
Pseudomonas colonisation	Inhaled colistin or gentamycin (conditional recommendation, low quality evidence	Inhaled colistin (1st line) (Grade of recommendation B) Inhaled gentamycin (2nd line) (Grade of recommendation B)	Single RCTs of individual antibiotics
Colonisation with non-pseudomonas organisms	Systemic macrolides (1st line): (conditional recommendation, moderate quality evidence) Nebulised gentamycin (2nd line) (conditional recommendation, low quality evidence)	Systemic macrolides (1st line) (Grade of recommendation A) Nebulised gentamycin (2nd line) (Grade of recommendation B)	Well conducted RCTs Single RCT
Duration of treatment	≥3 months	≥3 months	RCTs and meta-analyses
Eradication treatment for 1st isolation of organism	Pseudomonas isolation (conditional recommendation, very low quality evidence)	Pseudomonas isolation (Grade of recommendation D) MRSA (Grade of recommendation D)	One RCT and retrospective studies Expert opinion

Role of inhaled antibiotics beyond stable bronchiectasis:

Eradication treatment

Orriols et al.[41] studied nebulised tobramycin with intravenous ceftazidime for 2 weeks, followed by 3 months of inhaled tobramycin in NCFB patients after first Pseudomonas isolation. They reported higher bacterial eradication rates, fewer hospitalisations, and reduced exacerbation frequencies, but no lung function or quality of life improvements. Bronchospasm led to a 14% discontinuation rate [Table 9]. A meta-analysis of observational studies showed a 12-month eradication rate of 40%, with combined systemic and inhaled antibiotics achieving 48% compared to 27% with systemic antibiotics alone. It also showed fewer exacerbations but no reduction in hospitalisations.[42] Based on these findings, the 2017 ERS (conditional recommendation) and 2019 BTS guidelines 2019 (Grade of recommendation D) recommend eradication therapy for first Pseudomonas isolation, starting with 2 weeks of systemic antibiotics with or without inhaled antibiotics, followed by 3 months of inhaled therapy. The BTS guidelines also suggest eradication for first MRSA isolation based on expert opinion [Table 8]. Recommended inhaled antibiotics include colistin (1–2 million units BID), tobramycin (300 mg BID), and gentamicin (80 mg BID).[43,44]

Table 9.

Studies of inhaled antibiotics for eradication treatment and acute exacerbation in non-CF bronchiectasis

Study	Population	Intervention	Outcomes	Adverse effects*
Orriols et al. (2015)[41]	n=35, Age ≥18 years (+) 1st isolation of Pseudomonas aeruginosa	Intravenous ceftazidime + inhaled tobramycin 300 mg twice daily for 2 weeks followed by 3 months of inhaled tobramycin using PARI LC Plus jet nebuliser vs placebo	a. Bacterial eradication after 1 month: 90.9% vs 76.5%, p: 0.048 b. Bacterial eradication after 12 months of follow up: 55% vs 29% c. Exacerbation frequency: Decreased, 1.27 vs 2.5, p: 0.04 d. Number of hospitalisations per patient: 0.06 vs 0.47, p: 0.04 e. Days of hospitalisation per patient: Decreased, 0.90 vs 13.56, p: 0.03 f. Lung functions: No difference g. Quality of life scores: No difference	Bronchospasm (14%)
Bilton et al. (2006)[45]	n=53, Age: 18 to 80 years, Acute exacerbation (+) Pseudomonas aeruginosa in sputum	Oral Ciprofloxacin 750 mg twice daily + TIS 300 mg twice daily using Pari LC Plus Jet nebuliser vs placebo plus oral ciprofloxacin for 2 weeks	a. Cure rate at 21 days: No difference, p: 0.091 b. Sputum bacterial eradication: No difference, p: 0.18 c. Sputum bacterial density: Decreased	Wheezing(50%)
Ailiyaer et al. (2018)[46]	n=152, Age: 18 to 75 years, Acute exacerbation (+) Pseudomonas aeruginosa in sputum	Nebulised Amikacin 2 ml (0.2 g/ml) plus 3 ml normal saline twice daily using jet atomizer plus systemic antibiotic vs placebo nebuliser plus systemic antibiotic for 2 weeks	a. Sputum bacterial eradication: 51.4% vs 23.2%, p: 0.03 b. Quality of life scores: No difference c. Lung function: No difference	Bronchospasm (4%)

TIS: Tobramycin inhalation solution. *Adverse events mentioned are for the study group

During acute exacerbation episodes

Acute exacerbation of bronchiectasis is defined as worsening of at least three key symptoms for ≥48 hours, prompting a change in treatment, typically systemic antibiotic.[45] Inhaled antibiotics have been explored as adjuncts during Pseudomonas-related exacerbations [Table 9]. Bilton et al.[46] (N = 53) found that adding nebulised tobramycin to oral ciprofloxacin reduced sputum bacterial density but did not improve cure rates or eradication, with wheezing in 50% of cases. Ailiyaer et al.[47] (N = 152) reported higher sputum bacterial eradication (51.4%) with nebulised amikacin plus systemic antibiotics and no other clinical benefit with 4% experiencing bronchospasm.

CONCLUSION AND UNMET NEEDS

Long-term inhaled antibiotics benefit stable non-CF bronchiectasis patients, though trial results vary due to study heterogeneity. Frequent exacerbations, high sputum volume, and purulence predict better outcomes. Their role in pseudomonas eradication is promising, but efficacy in acute exacerbations remains uncertain. Future RCTs should include larger, diverse cohorts (children and elderly), standardised exacerbation criteria, high bacterial load, high exacerbation frequencies, continuous treatment regimens, longer follow-up, and comparisons of different inhaled antibiotics and delivery methods.

Research questions for future RCTs

1. Does a continuous dosing regimen of inhaled tobramycin improve long-term clinical outcomes compared to an intermittent (28-day on/off) regimen in non-CF bronchiectasis patients with chronic Pseudomonas aeruginosa colonisation?

   Study design: Multicentre RCT with 12–24 months study duration, enrolling patients with high exacerbation frequencies and sputum purulence

2. Which inhaled antibiotic (tobramycin, colistin, aztreonam, ciprofloxacin) is most effective in reducing bacterial load and exacerbations in NCFB?

   Study design: Head-to-head RCT with multiple arms comparing different inhaled antibiotics over 6–12 months.

3. Which inhaled antibiotic delivery system (jet nebuliser, vibrating mesh nebuliser, dry powder inhaler) provides the best drug deposition and clinical outcomes in NCFB?

   Study design: Crossover trial where patients receive different delivery methods in randomised order.

4. Does long-term inhaled antibiotic use contribute to the development of multi-drug-resistant (MDR) bacteria in NCFB patients?

   Study design: Observational cohort study tracking resistance patterns, clinical outcomes, and need for systemic antibiotics in patients on inhaled antibiotics for more than 12 months.

5. Do inhaled antibiotics improve long-term clinical outcomes compared to an intermittent regimen in paediatric and elderly non-CF bronchiectasis (NCFB) patients with chronic Pseudomonas aeruginosa colonisation?

   Study design: Multi-centre RCT with 12–24 months study duration.

Key message

Inhaled antibiotics benefit stable non-cystic fibrosis bronchiectasis patients with frequent exacerbations and aid in Pseudomonas aeruginosa eradication after first isolation. Key clinical traits associated with their effectiveness include frequent exacerbations, increased sputum production, and high sputum bacterial density at baseline.

Ethical clearance

Not needed as this is a review article.

However, the author acknowledges the ethical implications of long term inhaled antibiotics.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.