Table 1.
Characteristics of the Included Studies
| Study | Drug | Duration | Intervention vs Control Groups |
Primary Outcome | Secondary outcomes | ||||
|---|---|---|---|---|---|---|---|---|---|
| No. of Participants | Age, y | FEV1 % Predicted | P aeruginosa Present | Other Pathogens Present | |||||
| Aksamit et al (2018)21 (RESPIRE 2-28 da) | Ciprofloxacin DPI (32.5 mg) vs placebo twice/d | 12 mo | 171 (92 female, 79 male) vs 86 (52 female, 34 male) | 59.3 ± 14.2 vs 60.6 ± 13.7 | 56.4 ± 18.8 vs 56.2 ± 18.2 | 99 (58) vs 54 (63) | ≥ 1 prespecified microorganism for recruitment: Haemophilus influenzae, Moraxella catarrhalis, S aureus, S pneumoniae, Stenotrophomonas maltophilia, Burkholderia cepacia | Time to first exacerbation, frequency of exacerbations | Less stringent definition of an exacerbation microbiologic outcomes, QOL assessments (SGRQ and QOL-B), lung function |
| Aksamit et al (2019)21 (RESPIRE 2-14 d)a | Ciprofloxacin DPI (32.5 mg) vs placebo twice/d | 12 mo | 176 (96 female, 80 male) vs 88 (62 female, 26 male) | 60.4 ± 13.7 vs 60.4 ± 15.0 | 54.3 ± 17.3 vs 55.8 ± 18.6 | 107 (61) vs 55 (63) | ≥ 1 prespecified microorganism for recruitment: H influenzae, M catarrhalis, S aureus, S pneumoniae, S maltophilia, B cepacia | Time to first exacerbation, frequency of exacerbations | Less stringent definition of an exacerbation microbiologic outcomes, QOL assessments (SGRQ and QOL-B), lung function |
| Barker et al (2000)32 | Nebulized tobramycin (300 mg) vs placebo (1.25 mg quinine in saline) twice/d | 6 wk | 37 (23 female, 14 male) vs 37 (22 female, 15 male) | 66.6 ± 13.0 vs 63.2 ± 13.5 | 56.2 ± 21.2 vs 53.3 ± 22.1 | 37 (100) vs 37 (100) | No data | Change in P aeruginosa density (CFU/g) from baseline to wk 4 | Change in P aeruginosa density from baseline to wk 2 and to wk 6, investigator’s subjective assessment of change in patient general medical condition, percentage change in FEV1 and FVC % predicted, and safety measurements |
| Barker et al (2014)29 (AIR-BX 1) | Nebulized aztreonam (75 mg) vs placebo tid | 28 wk | 134 (84 female, 50 male) vs 132 (97 female, 35 male) | 64.2 ± 12.9 vs 64.9 ± 12.1 | 60.4 ± 22.6 vs 64.5 ± 18.7 | 112 (84) vs 105 (80) | History of NTM: 16 (12) vs 14 (10); no data for other organisms | Change in QOL-B RSS score from baseline to wk 4 | Change in QOL-B RSS score from baseline to wk 12, time to first exacerbation by wk 16, change in CFU/g, presence or absence of respiratory pathogens, changes in MIC of aztreonam |
| Barker et al (2014)29 (AIR-BX 2) | Nebulized aztreonam (75 mg) vs placebo tid | 28 wk | 136 (89 female, 47 male) vs 138 (101 female, 37 male) | 63.3 ± 14.2 vs 62.7 ± 13.3 | 63.8 ± 19.5 vs 63.4 ± 13.3 | 116 (85) vs 103 (75) | History of NTM: 8 (6) vs 12 (9); no data for other organisms | Change in QOL-B RSS score from baseline to wk 4 | Change in QOL-B RSS score from baseline to wk 12, time to first exacerbation by wk 16, change in CFU/g, presence or absence of respiratory pathogens, changes in MIC of aztreonam |
| De Soyza et al (2018)20 (RESPIRE 1-28 d)a | Ciprofloxacin DPI (32.5 mg) vs placebo twice/d | 12 mo | 141 (101 female and 40 male) vs 70 (52 female and 18 male) | 64.2 ± 12.1 vs 64 ± 13.5 | 59.48 ± 15.1 vs 61.7 ± 16.7 | 83 (59) vs 45 (64) | ≥ 1 prespecified microorganism for recruitment: H influenzae, M catarrhalis, S aureus, S pneumoniae, S maltophilia, B cepacia | Time to first exacerbation, frequency of exacerbations | Less stringent definition of an exacerbation microbiologic outcomes, QOL assessments (SGRQ and QOL-B), lung function |
| De Soyza et al (2018)20 (RESPIRE 1-14 d)a | Ciprofloxacin DPI (32.5 mg) vs placebo twice/d | 12 mo | 137 (88 female and 49 male) vs 68 (44 female and 24 male) | 65.2 ± 13.5 vs 65.5 ± 12.9 | 59.42 ± 16.7 vs 57.37 ± 15.5 | 83 (61) vs 41 (64) | ≥ 1 prespecified microorganism for recruitment: H influenzae, M catarrhalis, S aureus, S pneumoniae, S maltophilia, B cepacia | Time to first exacerbation, frequency of exacerbations | Less stringent definition of an exacerbation microbiologic outcomes, QOL assessments (SGRQ and QOL-B), lung function |
| Drobnic et al (2005)25 | Nebulized tobramycin (300 mg) vs placebo (0.9% saline) twice/d; crossover trial | 13 mo | 10 vs 10 in the PP population of 30 participants included in the ITT population (sex breakdown not reported) | Mean, 64.5 (range, 38-75) | 51.78 ± 16.5 | 10 (100) vs 10 (100) | No data | Not specifically stated, but presumed to be no. of exacerbations | No. of hospital admissions, No. of hospital admission days, antibiotic use, pulmonary function, SGRQ score, tobramycin toxicity, density of P aeruginosa in sputum, emergence of bacterial resistance, and emergence of other opportunistic bacteria |
| Guan et al (2023)27b | Nebulized TIS 300 mg vs placebo (normal saline) twice/d | 16 wk | 167 (109 female and vs 58 male) and 172 (112 female and 60 male) | 53.0 ± 13.0 vs 54.0 ± 12.0 | 60.9 ± 21.5 vs 63.6 ± 22.5 | 167 (100) vs 172 (100) | No data | Change from baseline in P aeruginosa density on d 29; QOL-B RSS score change from baseline | Time to the first exacerbation, frequency of exacerbations, rate of negative culture results on d 29, 24-h sputum volume and sputum purulence, change from baseline in BHQ, MIC on d 29 and 85, tobramycin blood concentration on d 1 and 28. |
| Haworth et al (2014)28 | Nebulized colistin (1 million International Units) vs placebo (0.45% saline) twice/d | 26 wk | 73 (46 female, 27 male) vs 71 (37 female, 34 male) | 58.3 ± 15.3 vs 60.3 ± 15.8 | 55.9 ± 24.3 vs 57.6 ± 24.9 | 73 (100) vs 71 (100) | H influenzae: 0 vs 1 (1%); S aureus: 3 (4%) vs 5 (7%); S pneumoniae: 2 (3%) vs 0; S maltophilia: 0 vs 0; M catarrhalis: 3 (4%) vs 2 (3%) | Time to exacerbation | Time to exacerbation (based on adherence recorded by the I-neb), severity of exacerbation, CFUs of P aeruginosa, 24-h sputum weight, SGRQ score, bronchoconstriction in 30 min after first dose of study drug, FEV1, sensitivity of P aeruginosa to colistin, CFUs of other potentially pathogenic organisms, and adverse event reporting |
| Haworth et al (2019)22 (ORBIT-3) | Liposomal ciprofloxacin (liposome encased ciprofloxacin [135 mg] and free ciprofloxacin [54 mg]) vs placebo (empty liposomes in 0.9% saline) once daily | 48 wk | 183 (127 female, 56 male) vs 95 (67 female, 28 male) | 64.3 ± 13.6 vs 66.7 ± 10.7 | 57.3 ± 21.9 vs 57.4 ± 20.2 | 183 (100) vs 95 (100) | S aureus: 31 (17%) vs 22 (23%); Escherichia coli and coliforms: 11 (6%) vs 5 (5%); S pneumoniae: 5 (3%) vs 3 (3%); H influenzae: 5 (3%) vs 1 (1%); M catarrhalis: 2 (1%) vs 0 | Time to first pulmonary exacerbation | No. and frequency of pulmonary exacerbations, no. of patients requiring IV antibiotics, QOL-B RSS score, change in P aeruginosa bacterial density (CFU/g) |
| Haworth et al (2019)22 (ORBIT-4) | Liposomal ciprofloxacin (liposome encased ciprofloxacin [135 mg] and free ciprofloxacin [54 mg]) vs placebo (empty liposomes in 0.9% saline) once daily | 48 wk | 206 (134 female, 72 male) vs 98 (63 female, 35 male) | 63.3 ± 13.6 ± vs 64.2 ± 12.6 | 62.6 ± 22.2 vs 59.8 ± 20.8 | 206 (100) vs 98 (100) | S aureus: 50 (24%) vs 23 (24%); E coli and coliforms: 9 (4%) vs 3 (3%); S pneumoniae: 10 (5%) vs 3 (3%); H influenzae: 7 (3%) vs 4 (4%) | Time to first pulmonary exacerbation | No. and frequency of pulmonary exacerbations, No. of patients requiring IV antibiotics, QOL-B RSS score, change in P aeruginosa bacterial density (CFU/g) |
| Haworth et al (2021)19b | Colistimethate sodium (CMS I-neb) vs placebo I-neb (0.45% saline) twice/d | 12 mo | 176 (123 female and 53 male) vs 197 (126 female and 71 male) | 64.2 ± 14.9 vs 64.2 ± 13.1 | 62.4 ± 20.7 vs 64.5 ± 18.9 | 176 (100) vs 197 (100) | No data | Mean annual exacerbation rate | Mean annual severe exacerbation rate, time to first exacerbation, change in SGRQ total score, change in P aeruginosa sputum density, P aeruginosa resistance to colistimethate sodium |
| Loebinger et al (2021)26b | TIP in 3 cohorts with 2 intervention groups (cyclical vs continuous; 84 mg, 140 mg, or 224 mg daily) vs placebo | 112 d | 86 (33 male and 53 female) vs 21 (8 male and 13 female) | 62.52 ± 14.12 vs 67.23 ± 11.00 | 59.71 ± 21.52 vs 59.50 ± 18.24 | 86 (100) vs 21 (100) | No data | Change from baseline to d 29 in P aeruginosa density in sputum | Antimicrobial efficacy of TIP, effect of different doses of TIP and different regimens on pulmonary exacerbations, efficacy profile of different doses of TIP and different regimens as measured by antipseudomonal antibiotic use |
| Murray et al (2011)24 | Nebulized gentamicin (80 mg) vs placebo (0.9% saline) twice/d | 15 mo | 2 vs 33 randomly assigned; 27 (18 female, 9 male) vs 30 (15 female, 15 male) completed and included in the analysis | Median (IQR), 58 (53-67) vs 64 (56-69) | median (IQR): 72.9 (60-81.2) vs 63.4 (45.5-80.4) | 13 (48) vs 11 (37) | H influenzae: 11 (41%) vs 15 (50%); S aureus: 2 (7%) vs 1 (3%); S pneumoniae: 1 (4%) vs 0; M catarrhalis: 0 vs 2 (7%); coliforms: 0 vs 1 (3%) | Quantitative bacteriology in CFU/g | Sputum purulence and 24-h volume, pulmonary function test results, exercise capacity, LCQ and SGRQ scores, exacerbation frequency, inflammatory biomarkers |
| Orriols et al (1999)30 | Nebulized ceftazidime (1,000 mg) and tobramycin (100 mg) twice/d vs standard care | 12 mo | 7 (1 female, 6 male) vs 8 (4 female, 4 male) | Mean, 62.0 (SEM 8.5) vs 61.4 (10.3) | 62.3 (SEM 19.9) vs 56.2 (21.4) | 7 (100) vs 8 (100) | No data | Not specifically stated, but presumed to be no. of hospital admissions | Length of hospitalization (d), use of oral antibiotics, FVC, FEV1, Pao2, Paco2, drug toxicity, and emergence of bacterial resistance |
| Serisier et al (2013)23 (ORBIT-2) | Liposomal ciprofloxacin (liposome encased ciprofloxacin [135 mg] and free ciprofloxacin [54 mg]) vs placebo (empty liposomes in 0.9% saline) once daily | 24 wk | 20 (10 female, 10 male) vs 22 (13 female, 9 male) | 70 ± 5.6 vs 59.5 ± 13.2 | 60.7 ± 24.1 vs 53.1 ± 22.7 | 20 (100) vs 22 (100) | Klebsiella: 2 (10%) vs 2 (9%); Ochrobactrum anthropic: 0 vs 2 (9%) | Mean change in sputum P aeruginosa bacterial density (CFU/g) from baseline to end of first treatment cycle (28 d) | Time to first pulmonary exacerbation, FEV1, 6MWT, SGRQ score, safety, and tolerability |
| Terpstra et al (2022)33b | Nebulized TIS 300 mg vs placebo (NaCl 0.9%) once daily | 52 wk | 26 (13 female and 13 male) vs 26 (17 female and 9 male) | 67.9 ± 6.6 vs 64.1 ± 14.0 | 65.9 ± 24.9 vs 70.5 ± 24.0 | 5 (19.2) vs 9 (34.6) | H influenzae: 7 (26.9) vs 9 (34.6); S aureus: 4 (15.4%) vs 2 (7.7%); S pneumoniae 0 (0%) vs 1 (3.8%); other: 10 (38.4%) vs 5 (19.3%) | No. of exacerbations during the 1-y treatment period | Time to next exacerbation, change in lung function, change in QOL measurements based on LRTI-VAS, QOL-B and the LCQ score |
| TR02-107 (NCT00775138)34 | Nebulized liposomal amikacin (280 mg and 560 mg) vs placebo (empty liposomes in 1.5% saline) once daily | 56 d | 24 (10 female, 14 male) vs 19 (11 female, 8 male) vs 19 (9 female, 10 male)a | 49.9 ± 21.1 vs 58.5 ± 16.0 vs 49.4 ± 13.3a | 64.5 ± 20.7 vs 71.4 ± 23.9 vs 62.6 ± 15.7a | 24 (100) vs 19 (100) vs 19 (100)a | No data | Safety of liposomal amikacin as measured by proportion of adverse events, change in oxygen saturations, change in FEV1 | Frequency of cough with expectoration, PSSS, SGRQ score, bacterial density of P aeruginosa (CFU/g), pulmonary exacerbations |
| Wilson et al (2013)31 | Ciprofloxacin DPI (32.5 mg) vs placebo twice/d | 84 d | 60 (39 female and 21 male) vs 64 (43 female and 21 male) | 64.7 ± 11.8 vs 61.4 ± 11.9 | 57.2 ± 13.7 vs 54.6 ± 14.8 | 32 (53) vs 35 (55) | H influenzae: 14 (23%) vs 16 (25%); S aureus: 8 (13%) vs 17 (27%); S pneumoniae: 7 (12%) vs 2 (3%); M catarrhalis: 5 (8%) vs 3 (5%) | Effect of ciprofloxacin DPI on total bacterial density of predefined potential respiratory pathogens in sputum (CFU/g) after the 28-d treatment period | Time to exacerbation; emergence of new potential respiratory pathogens; emergence of resistance among baseline pathogens; changes in inflammatory biomarkers; change in 24-h sputum volume and color; changes in FEV1, FVC, and SGRQ score at d 29, 56, and 84; adverse events; results of physical examinations; vital signs; and laboratory analyses |
Data are No. (%) or mean ± SD, unless otherwise specified. 6MWT = 6-min walk test; BHQ = Bronchiectasis Health Questionnaire; CFU = colony-forming units; CMS = colistimethate sodium; DPI = dry powder for inhalation; IQR = interquartile range; ITT = intention-to-treat; LCQ = Leicester Cough Questionnaire; LRTI-VAS = lower respiratory tract infections visual analog scale; MIC = minimum inhibitory concentration; NTM = nontuberculous mycobacterial infection; QOL = quality of life; QOL-B = Quality of Life Questionnaire-Bronchiectasis; PP = per protocol; PSSS = pulmonary symptom severity score; RSS = respiratory symptoms scale; SEM = standard error of the mean; SGRQ = St. George Respiratory Questionnaire; TIP = tobramycin inhalation powder; TIS = 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.