Current state of development of inhaled antibiotic agents for non-cystic fibrosis bronchiectasis

Agent [ref.]nCurrent phase of developmentPrimary outcomeDurationPatient populationMain resultsSafety
Amoxicillin [78–80]6 (78); 3 (79); 5 (80)Three open label studies following failure of oral antibioticsSputum purulenceContinuous; 4 months/16 weeksBronchiectasis patients with purulent sputum that failed to clear following oral amoxicillinReduced sputum purulence; reduced neutrophil elastase activity ; reduced sputum volume; improved PEFR.No issues identified.
Tobramycin [81]A: 37; P: 37Phase II studyP. aeruginosa bacterial load28 days treatment (total duration 8 weeks)P. aeruginosa-colonised patients; mean age 66 versus 63 years; FEV1 mean 56 versus 53%Significant reduction in P. aeruginosa load (mean difference 4.56 log10 cfu·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.
Gentamicin [82]A: 27; P: 30Single-blind randomised controlled trialBacterial load12 monthsPatients colonised with any pathogens in at least three sputum samples in the preceding 12 months; two exacerbations in the previous year; able to tolerate test dose of gentamicin; FEV1 >30% predicted; exsmokers of >1 year; not on long-term antibiotics.Significant difference in bacterial load at 12 months (2.96 log10 cfu·mL−1 versus 7.67  log10 cfu·mL−1, p<0.0001); reduction in exacerbations (median 0 in the gentamicin group, 1.5 in the 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Colistin [83]A: 73; P: 71Phase III double-blind randomised controlled trialTime to first exacerbation6 months (patients withdrawn following exacerbation)P. aeruginosa-colonised patients (two or more positive cultures in 12 months) and within 21 days of completing antipseudomonal antibiotics for an exacerbation.Missed primary end-point (colistin 165 days, placebo 111 days, p=0.11); improved SGRQ (mean difference −10.5 points, p=0.006); improved time to first exacerbation in patients taking >80% of doses.Five patients (7%) developed bronchoconstriction leading to discontinuation; no resistant strains at follow-up.
Aztreonam [84]AIR-BX1: A: 134; P: 132. AIR-BX2: A: 136; P: 1382× phase III double-blind randomised controlled trialQOL-B questionnaire score at week 4Two 28 day treatment courses with alternating 28 day off treatmentPositive 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 (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.AIR-BX1 adverse events leading to discontinuation: 22 versus 6%; AIR-BX2- adverse events leading to discontinuation: 10 versus 5%.
Ciprofloxacin DPI [86]A: 60; P: 64Phase II double blind randomised controlled trialBacterial load28 days treatment with follow-up to 84 daysIdopathic or post-infective bronchiectasis; two or more exacerbations in the previous 12 months (one hospitalisation); able to produce sputum; culture positive for target microorganisms.Mean difference in bacterial load −3.62 log10 cfu·mL−1 versus −0.27 log10 cfu·mL−1, p<0.001; no significant differences in proportion of patients with exacerbations (36.7 versus 39.1%, p=0.6); no significant difference in 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.
Liposomal ciprofloxacin [87]A: 20; P: 22Phase II study double blind randomised controlled trialBacterial 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 log10 cfu·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); median time to pulmonary exacerbations reduced in the per protocol population (p=0.046).No significant difference in minimal inhibitory concentrations to ciprofloxacin at day 28; no increase in adverse events.
  • PEFR: peak expiratory low rate; A: active; P: placebo; P. aeruginosa: Pseudomonas aeruginosa; FEV1: forced expiratory volume in 1 s; cfu: colony forming units; SGRQ: St. Georges Respiratory Questionnaire; LCQ: Leicester Cough Questionnaire; QOL-B: quality of life bronchiectasis questionnaire; DPI: dry powder for inhalation; MIC: minimum inhibitory concentration.