TABLE 2.
Summary of randomised controlled trials (RCTs) of inhaled antibiotics for bronchiectasis
| Agent and study | Subjects (n) | Study design | Primary outcome | Duration | Study population | Main results | Safety |
|---|---|---|---|---|---|---|---|
|
Ciprofloxacin DPI Wilson et al. (2013) [76] |
A: 60 P: 64 |
Phase 2 double-blind RCT | Bacterial load | 84 days (28-day treatment with follow-up) | ≥2 exacerbations in previous year; culture positive for target microorganisms | Mean difference in bacterial load −3.62 versus −0.27 log10CFU·mL−1 (p<0.001); no significant differences in proportion of patients with exacerbations (36.7% versus 39.1%; p=0.6) and SGRQ (mean difference −3.56; p=0.059) | 10% of patients developed resistance (MIC >4 mg·L−1) in the ciprofloxacin group; no difference in adverse events between groups |
|
Ciprofloxacin DPI De Soyza et al. (2018) RESPIRE 1 [77] |
14-day on/off A: 137 P: 68 28-day on/off A: 141 P: 70 |
Phase 3 double-blind RCT | Time to first exacerbation, frequency of exacerbations | 12 months (14- or 28-day on/off-treatment cycles) | ≥2 exacerbation in previous year; culture positive for predefined microorganisms | 14-day on/off cycle: significantly prolonged time to first exacerbation (median >336 versus 186 days; HR 0.53, 97.5% CI 0.36–0.80; p=0.0005); reduced frequency of exacerbation (IRR 0.61, 97.5% CI 0.40–0.91; p=0.0061); 28-day on/off cycle: no significant differences in primary end-points | No difference in adverse events between groups |
|
Ciprofloxacin DPI Asakamit et al. (2018) RESPIRE 2 [78] |
14-day on/off A: 176 P: 88 28-day on/off A: 171 P: 86 |
Phase 3 double-blind RCT | Time to first exacerbation, frequency of exacerbations | 12 months (28-day on/off-treatment cycles) | ≥2 exacerbations in previous year; culture positive for predefined microorganisms | Missed primary end-point: prolonged time to first exacerbation (HR 0.87, 95% CI 0.62–1.21; p=0.40 in 14-day on/off and HR 0.71, 99% CI 0.39–1.27; p=0.051 in 28-day on/off) and reduced frequency of exacerbations (IRR 0.83, 95% CI 0.59–1.17; p=0.29 in 14-day on/off and IRR 0.55, 99% CI 0.30–1.02; p=0.001 in 28-day on/off) | No difference in adverse events between groups |
|
Liposomal ciprofloxacin Serisier et al. (2013) ORBIT-2 [79] |
A: 20 P: 20 |
Phase 2 double-blind RCT | Bacterial load after first 28-day treatment cycle with intervening 28-day off periods | 24 weeks (three 28-day treatment cycles) | P. aeruginosa-colonised patients; ≥2 exacerbations in previous 12 months | Reduction in P. aeruginosa bacterial load −4.2 versus −0.08 log10CFU·mL−1 (p=0.002); reduced number of exacerbations in the active treatment group (OR 0.2, 95% CI 0.04–0.89; p=0.027) | No significant difference in MICs to ciprofloxacin at day 28; no increase in adverse events |
|
Liposomal ciprofloxacin Haworth et al. (2019) ORBIT-3 and ORBIT-4 [80] |
ORBIT-3 A: 183 P: 95 ORBIT-4 A: 206 P: 98 |
Phase 3 double-blind RCT | Time to first exacerbation | 48 weeks (six 28-day on/off-treatment cycles) | ≥2 exacerbations in previous year; chronic P. aeruginosa infection | Median time to first exacerbation: 230 versus 158 days (HR 0.72, 95% CI 0.53–0.97; p=0.032) in ORBIT-4; 214 versus 136 days (HR 0.99, 95% CI 0.71–1.38; p=0.97) in ORBIT-3; and 222 versus 157 days (HR 0.82, 95% CI 0.65–1.02; p=0.074) in a pooled analysis of both trials | No difference in adverse events between groups |
|
Aztreonam Barker et al. (2014) AIR-BX1 and AIR-BX2 [81] |
AIR-BX1 A: 134 P: 132 AIR-BX2 A: 136 P: 138 |
Two phase 3 double-blind RCTs | QOL-B score at week 4 | Two 28-day treatment courses with alternating 28 days off treatment | Positive sputum for P. aeruginosa or other Gram-negative organisms (excluding H. influenzae); FEV1 >20% predicted; chronic sputum production | No difference in QOL-B at week 4 (mean difference 0.8, 95% CI −3.1–4.7; p=0.7 in AIR-BX1 and 4.6, 95% CI 1.1–8.2; p=0.011 in AIR-BX2); no difference in QOL-B in both studies at week 12 (p=0.56 in both studies); no difference in time to first exacerbation | Adverse events leading to discontinuation: AIR-BX1 22% versus 6%; AIR-BX2 10% versus 5% |
|
Tobramycin Barker et al. (2000) [82] |
A: 37 P: 37 |
Phase 2 double-blind RCT | P. aeruginosa bacterial load at week 4 | 6 weeks (28-day treatment) | P. aeruginosa-colonised patients | Significant reduction in P. aeruginosa load (mean difference 4.56 log10CFU·mL−1; p<0.01); 13/37 cleared P. aeruginosa from sputum; no significant change in FEV1 (p=0.41) | Increased dyspnoea, chest pain and wheezing; new resistance to tobramycin in 4/36 |
|
Tobramycin Guan et al. (2022) TORNASOL [83] |
A: 167 P: 172 |
Phase 3 double-blind RCT | P. aeruginosa bacterial load and QOL-B Respiratory symptoms score on day 29 | 16 weeks (two cycles of 28 days on/off treatment) | ≥1 exacerbations in previous 2 years; chronic P. aeruginosa infection | P. aeruginosa bacterial load mean difference 1.74 log10CFU·mL−1 (p<0.001); QOL-B Respiratory symptom score mean difference 7.9 (p<0.001) | Adverse events leading to discontinuation: 6.2% (tobramycin) versus 2.8% (placebo) |
|
Tobramycin Terpstra et al. (2022) BATTLE [84] |
A: 26 P: 26 |
Phase 3 double-blind RCT | Frequency of exacerbation | 12 months | ≥2 exacerbations in previous year; culture positive for predefined microorganisms | Missed primary end-point: rate ratio 0.74, 95% CI 0.49–1.14 (p=0.15) | 8.8% of tobramycin group discontinued study due to respiratory symptoms in first 4 weeks |
|
Tobramycin inhalation powder Loebinger et al. (2021) iBEST [85] |
A: 86 P: 21 |
Phase 2 double-blind RCT | P. aeruginosa bacterial load on day 29 | Treatment for 16 weeks plus follow-up for 8 weeks | P. aeruginosa-colonised patients | Primary end-point was met in all three doses: P. aeruginosa bacterial load (log10CFU·mL−1) −2.5 at 84 mg (p=0.0004), −2.8 at 140 mg and −3.8 at 224 mg (p=0.0001 for all) | 8.8% of tobramycin group discontinued study due to respiratory symptoms in first 4 weeks |
|
Gentamicin Murray et al. (2011) [86] |
A: 27 P: 30 |
Single-blind RCT | Bacterial load | 12 months | Patients colonised with any pathogens in at least three sputum samples in the previous 12 months; 2 exacerbations in the previous year; able to tolerate test dose of gentamicin; FEV1 >30% predicted; ex-smokers of >1 year; not on long-term antibiotics | Significant difference in bacterial load at 12 months (2.69 versus 7.67 log10CFU·mL−1; p<0.0001); reduction in exacerbations (median 0 in gentamicin group versus 1.5 in saline group; p<0.0001); improved SGRQ and LCQ scores; reduced airway inflammation | Bronchospasm in 21.9%; two withdrawals; elevated serum gentamicin levels required dose reduction in one patient; no resistant isolates detected |
|
Colistin Haworth et al. (2014) [87] |
A: 73 P: 71 |
Phase 3 double-blind RCT | Time to first exacerbation | 6 months | P. aeruginosa-colonised patients (≥2 positive cultures in 12 months) and within 21 days of completing antipseudomonal antibiotics for exacerbation | Missed primary end-point (colistin 165 days versus placebo 111 days; p=0.11); improved SGRQ (mean difference −10.5; p=0.006); improved time to first exacerbation in patients taking >80% of doses | Five (7%) patients developed bronchoconstriction leading to discontinuation; no resistant strains at follow-up |
DPI: dry powder inhaler; A: active; P: placebo; SGRQ: St George's Respiratory Questionnaire; MIC: minimum inhibitory concentration; HR: hazard ratio; IRR: incident rate ratio; P. aeruginosa: Pseudomonas aeruginosa; QOL-B: Quality of Life Bronchiectasis; H. influenzae: Haemophilus influenzae; FEV1: forced expiratory volume in 1 s; LCQ: Leicester Cough Questionnaire.