The efficacy and safety of Inhaled antibiotics for the treatment of bronchiectasis in adults – A systematic review and meta-analysis

Dr Irena F Laska MBBS, Ms Megan L Crichton MFM, Dr Amelia Shoemark PhD, Professor James D Chalmers PhD

1 Scottish Centre for Respiratory Medicine, University of Dundee, Dundee, UK

Corresponding author: Professor James D Chalmers, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY. jchalmers@dundee.ac.uk

Keywords: Bronchiectasis, antibiotics, ciprofloxacin, exacerbations, meta-analysis

Acknowledgements: We thank Mike Lonergan for statistical advice. We thank all authors and study sponsors that provided unpublished data for inclusion in this meta-analysis.

© 2019. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/

Abstract

Background: Whilst use of inhaled antibiotics is the standard of care in cystic fibrosis, there is limited evidence to support use of inhaled antibiotics in patients with bronchiectasis not due to cystic fibrosis.

Methods: We conducted a systematic review and meta-analysis of all inhaled antibiotic randomised controlled trials in adult bronchiectasis patients with chronic respiratory tract infections to determine efficacy and safety. The review was registered on PROSPERO CRD42019122892. Publications meeting inclusion criteria were identified via database searches including MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and Web of Science. Randomized controlled trials of inhaled antibiotics were included if patients were enrolled during a period of disease stability and the outcomes of each study met at least one of the endpoints of interest. Studies in cystic fibrosis were excluded. Each study was independently reviewed for methodological quality using the Cochrane risk of bias tool. Random-effects meta-analysis was used to pool individual studies. Heterogeneity was assessed using I2

Findings: Sixteen trials (n=2597 patients) were included for analysis. The mean reduction of colony forming units per gram of sputum with inhaled antibiotics was -2·32 log units (95% CI -3·20 – -1·45; p<0·00001). Inhaled antibiotics significantly reduced exacerbation frequency, rate ratio 0·81 (95% CI 0·67 – 0·97; p=0·02) and the proportion of patients experiencing at least one exacerbation, risk ratio 0·84 (95% CI 0·73 – 0·96; p=0·02. Neither the Quality of Life Bronchiectasis questionnaire or St. Georges Respiratory Questionnaire improved above the minimal clinically important difference. There was no significant difference in treatment emergent adverse effects, odds ratio (OR) 0·94 (95% CI 0·68 – 1·32; p=0·74) or bronchospasm, OR 0·91 (95% CI 0·64 – 1·29; p=0·39). Emergence of bacterial resistance was evident, risk ratio 2·04 (95% CI 1·55 – 2·67; p<0·00001). Heterogeneity between trials was evident in most analyses, but subgroup analyses by antibiotic type, P. aeruginosa status, trial duration and risk of bias supported the overall findings.

Interpretation: Inhaled antibiotics are well tolerated, reduce bacterial load and achieve a small but statistically significant reduction in exacerbation frequency without clinically significant improvements in quality of life.

Funding: British Lung Foundation through the GSK/British Lung Foundation Chair of Respiratory Research and European Respiratory Society through the EMBARC2 consortium. EMBARC2 is supported by project partners Chiesi, Grifols, Insmed, Novartis and Zambon.

RESEARCH IN CONTEXT PANEL

Evidence before this study

Two investigators searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and Web of Science using the search strategy described in the online supplement. Searches were conducted from 1990 to 30th January 2019 for trials on the long-term use of inhaled antibiotics in adult patients with bronchiectasis and chronic respiratory tract infections. Studies in patients with cystic fibrosis were excluded. No language restrictions were applied. Searches were supplemented with review of reference lists and by reviewing previous meta-analyses and guidelines. Clearly ineligible studies were excluded based on abstract review alone.

We identified 464 references and after exclusion of non-relevant studies we identified 15 randomized controlled trials comparing long-term treatment with inhaled antibiotics (>1 months’ duration) to placebo or other comparator where the primary outcome was defined as critical or important as per the European Bronchiectasis guidelines. A search of clinicaltrials.gov found one further (unpublished) trial eligible for our analysis. The risk of bias for each trial was assessed using the Cochrane collaboration risk of bias tool and the findings are presented in the online supplement.

European Respiratory Society guidelines suggest to prescribe inhaled antibiotics to patients with a history of 3 or more exacerbations per year and chronic infection with Pseudomonas aeruginosa. The recommendation is conditional and acknowledges that further evidence is required. A previous meta-analysis by Brodt et al. was identified but was conducted prior to the reporting of several recent large randomized trials.

Added value of this study

Our data from 2597 patients enrolled across 16 international randomized clinical trials suggest that inhaled antibiotic treatment compared to placebo for at least one month significantly reduces bacterial load and reduces exacerbation frequency by 19%. There was no significant increase in overall adverse events; however, aztreonam was associated with increased adverse events, serious adverse events and adverse events leading to discontinuation. Antibiotic resistance was increased with therapy. Bronchospasm was only significantly increased with inhaled aminoglycosides. Inhaled antibiotics appeared to have no consistent effect on 24hr sputum volume, six-minute walk test, FEV1 or quality of life questionnaires and symptoms.

Implications of all the available evidence

European bronchiectasis guidelines recommend inhaled antibiotics as first line treatment for patients with P. aeruginosa infection and frequent exacerbations. Our data suggest that inhaled antibiotics consistently achieve reductions in bacterial load and bacterial eradication, but this translates into a small but statistically significant impact on exacerbation frequency. The clinical significance of the pooled exacerbation benefit observed in our study is uncertain. Despite the heterogeneity our data suggest inhaled antibiotics are generally safe, well tolerated and beneficial in terms of exacerbation reduction for long-term maintenance therapy.

Our results, including those of subanalyses and the relative homogeneity of inclusion criteria in the 16 trials conducted to date suggest that it is likely that further trials in this patient population would achieve similar results. Further research is required to identify an inhaled antibiotic responsive population and to optimise future trial designs.

Introduction

Bronchiectasis is a chronic lung disease characterized by inflammation of the airways, mucociliary dysfunction, mucus plugging and progressive structural damage.1 Patients commonly develop persistent cough, sputum production and recurrent infections accompanied by the radiological findings of dilated and thickened bronchi.2,3 Potential causes of bronchiectasis include respiratory tract infections, non-tuberculous mycobacteria, allergic bronchopulmonary aspergillosis, immunodeficiencies, ciliary dysfunction, and autoimmune diseases including rheumatoid arthritis, and inflammatory bowel disease.4

The disease process can lead to chronic infections, most commonly with Haemophilus influenzae or Pseudomonas aeruginosa, and less frequently with Streptococcus pneumoniae, Staphylococcus aureus, Moraxella catarrhalis and other enteric Gram-negative organisms.5–7 Chronic infections, particularly with P. aeruginosa, potentiate airways inflammation, and are associated with more frequent exacerbations and hospital admissions, reduced quality of life, increased mortality, and increased healthcare costs.6,8,9

Inhaled antibiotics are part of the standard of care in cystic fibrosis (CF) with chronic P. aeruginosa infection.10 The use of long-term inhaled antibiotics has been shown reduce exacerbations and the decline in lung function, possibly by decreasing bacterial load and therefore airway inflammation.11 An inhaled route of administration can provide consistent deposition of concentrated antibiotic levels in ventilated areas of the lung with a lower risk of toxicity or systemic adverse effects encountered with antibiotics administered via other routes.12 This could be particularly advantageous for patients with bronchiectasis not due to CF given that it is more prevalent in an older, frailer population with multiple comorbidities.13 The adverse effects of inhaled antibiotics are mostly localised to the lung, such as cough and bronchospasm, and there is potential for the development of microbial resistance.12

To date the evidence for the role of inhaled antibiotics in bronchiectasis has not been firmly established, although the 2017 European Respiratory Society guidelines provided a conditional recommendation in favour of their use in patients with P. aeruginosa infection.14 This guideline and a prior meta-analysis were completed before the publication of the two largest programmes of inhaled antibiotics in bronchiectasis.12,14–17 We therefore conducted a systematic review and meta-analysis of randomised controlled trials to assess the efficacy and safety of inhaled antibiotics in adult patients with stable bronchiectasis not due to CF and chronic respiratory tract infections.

Methods

This systematic review and meta-analysis were conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) recommendations.18 The review protocol was prospectively registered at PROSPERO - CRD42019122892. The objective was to determine the efficacy and safety of inhaled antibiotics for the long-term treatment of stable bronchiectasis patients with chronic infections.

Data Sources and Search Strategy

Two investigators (MLC and JDC) conducted database searches using MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and Web of Science. The period for the database searches was between 1990 to 30th January 2019. Further details of the search strategy can be found in the online supplement. Searches were supplemented by reviewing the reference lists of the publications, previous meta-analyses and guidelines. Clearly ineligible studies were excluded based on abstract review. We also conducted a search of the clinicaltrials.gov registry using “bronchiectasis” as the only search term.

Study inclusion criteria

A priori we considered for inclusion trials that met the following criteria: 1) randomized controlled trials with a placebo or other comparator, 2) inclusion of adult patients with bronchiectasis diagnosed by computed tomography or bronchography, 3) treatment with inhaled antibiotics in stable patients, defined by the absence of exacerbation at baseline (definitions used are shown in table E1 online), 4) study duration of at least 4 weeks, and 5) assessment of at least one of the clinical endpoints of interest (listed below). Exclusion criteria were: 1) trials that included CF patients, 2) trials in children, and 3) treatment administered during an acute exacerbation of bronchiectasis only. Study selection was performed by two reviewers with discrepancy resolved by consensus discussion.

Data extraction and quality assessment

Two reviewers extracted endpoints of interest in a blinded fashion (IFL and MLC). Data from each study were tabulated and checked by a third independent abstractor prior to inclusion in the analysis. We used a pre-designed spread sheet to collect study data in a standardised way. For categorical outcomes we extracted N and denominator, and for continuous outcomes we extracted sample size, mean/median, and precision of estimate (standard deviation, standard error, 95% confidence intervals (95% CI), or interquartile range) based on the information provided within studies. For effect estimates we extracted the number of patients in each group, effect estimate, and confidence intervals. Where more than one set of results were reported, we selected the intention to treat datasets. Where results were not reported in a format suitable for meta-analysis we used recommended methods from the Cochrane collaboration to extract or estimate effects including: 1) contacting study authors and pharmaceutical company sponsors to request unpublished data, 2) using formulae to extract standard errors, standard deviations or confidence intervals from the presented data, and 3) conversion of medians to estimated mean and standard deviation as previously described.19 Where data had been estimated, sensitivity analyses excluding such data were performed to check the influence of any assumptions on the reported pooled effects. Two manuscripts reported two regimens of inhaled ciprofloxacin and compared these against a pooled placebo containing data from both 14-day and 28-day arms. Where results were reported for the matching placebo, the effect estimates versus matching placebo were reported. Where these were not available, results against pooled placebo were used in the meta-analysis.15,16

Two reviewers (IL and MLC) independently assessed the risk of bias using the Cochrane collaboration risk of bias tool which takes account of: allocation sequence generation, concealment of allocation, blinding of participants and investigators, incomplete outcome reporting, selective outcome reporting, and other sources of bias. Each potential source of bias was graded as yes, no or unclear allowing a determination of whether studies were considered at high, low or moderate risk of bias. Disagreement regarding quality assessments was resolved by a third reviewer (AS).

Endpoints

We pre-specified endpoints for efficacy based on expert consensus of those that were selected by the European Bronchiectasis Guidelines panel as critical or important.14 The endpoints selected were: frequency of exacerbations, time to first exacerbation, number of patients with at least one exacerbation, frequency of severe exacerbations (defined as those requiring hospitalization or treatment with intravenous antibiotics), quality of life, bacterial eradication from sputum, bacterial load, sputum volume, change in forced expiratory volume in 1 second (FEV1), mortality, and six-minute walk distance. Adherence to treatment was also evaluated.

Safety endpoints assessed were: bacterial resistance in sputum, which was defined as the proportion of bacterial isolates with a minimum inhibitory concentration (MIC) above the resistant breakpoint, and adverse events, which were subdivided into: total adverse events, treatment emergent serious adverse events, adverse events leading to treatment discontinuation, and bronchospasm as an adverse event of special interest.

Data analysis

We performed meta-analyses where sufficient data were reported for endpoints. For dichotomous outcomes data are presented as pooled risk ratios or odds ratios and 95% CI. Continuous variables are presented as mean differences with 95% CI. Effect estimates were pooled by the inverse of their variance and are presented as pooled effect estimates (hazard ratios or rate ratios) with corresponding 95% CI. All analyses used random effects meta-analysis using the method of DerSimonian and Laird due to the heterogeneity of study designs.20 The I2 statistic, representing the percentage of variation across studies that is due to heterogeneity rather than chance, was used to describe heterogeneity between studies and was calculated as previous described.21 Results are presented as 0-30% (low heterogeneity), 30-60% (moderate heterogeneity) and >60% (high heterogeneity) as recommended by the Cochrane handbook. Planned subgroup analyses were as follows: antibiotic agent (fluoroquinolones, aminoglycosides, colistin and aztreonam), trial duration (> six months), study quality (analysis restricted to high quality studies only), and baseline infection status (P. aeruginosa vs other pathogens). Meta-analyses were conducted using Revman version 5·3 (Cochrane collaboration).

Role of the funding source

The funding sources had no role in the study design, collection, analysis, or interpretation of the data, or writing the report. All authors (IFL, MLC, AS and JDC) had full access to the raw data. The corresponding author had full access to all of the data and the final responsibility to submit for publication.

Results

The search identified 464 references, which were reduced to 433 after removal of duplicates and secondary analyses of the same datasets. After applying the inclusion and exclusion criteria, eleven references involving 15 studies were selected for the meta-analysis.15–17,22–29 One manuscript described two trials of inhaled aztreonam (AIR-BX1 and 2).25 Two manuscripts described four trials of dry powder ciprofloxacin separated into 14 day on-off and 28 day on-off cycles (RESPIRE 1 and RESPIRE 2) which were treated as independent studies and one manuscript described two studies of inhaled liposomal ciprofloxacin (ORBIT 3 and 4).15–17 A search of clinicaltrials.gov identified one study of inhaled amikacin versus placebo, for which unpublished data were obtained. This allowed inclusion of 16 trials in total. The flow chart of the study and reasons for exclusion of specific references are shown in figure 1.

The characteristics of the included studies are shown in table 1. Most studies were conducted in typical bronchiectasis populations of predominantly female patients with a mean age of 60-70 years. Seven studies were limited to patients with P. aeruginosa infection only17,22,24,26–28 while the remainder included patients with organisms other than P. aeruginosa15,16,23,25,29; however, P. aeruginosa was the most frequently isolated organism in all of the studies. Study durations ranged from four weeks to one year. The primary outcomes were highly variable, but the most common were bacterial load measured in colony forming units per gram (CFU/g), time to first exacerbation, frequency of exacerbations, and quality of life.15–17,25,28

Table E2 online lists all analyses undertaken and the results of subanalyses. The major findings are summarised below. The results of the quality assessment are shown in Table E3 online.

Microbiological outcomes

Nine studies17,21-23,25,26 provided data on bacterial load demonstrating a consistent reduction in CFU/g of sputum with inhaled antibiotic treatment (figure 2). The mean reduction from the meta-analysis was -2·32 log units (95% CI -3·20 – -1·45; p<0·00001) with a high degree of heterogeneity, I2=91%. The effect for fluoroquinolones was -2·15 log units (95% CI -2·77 – -1·54; p<0·00001), I2=36%, four studies and for aminoglycosides, -2·45 log units (95% CI -6·55 – 1·64; p=0·24), I2=99%, two studies. Data for all nine studies were presented for a four-week time point.

Bacterial eradication from sputum, defined by the absence of the baseline pathogen on the end of treatment sputum sample, was increased with inhaled antibiotic treatment, OR 2·43 (95% CI 1·44 – 4·08; p=0·0008), with high degree of heterogeneity I2=73%, n=1693 patients.

Exacerbation endpoints

Studies reported different exacerbation endpoints including frequency of exacerbations over follow-up expressed as rate ratios, time to first exacerbation, number of patients experiencing at least one exacerbation, and the frequency and number of severe exacerbations, defined as those requiring hospitalization or intravenous antibiotics.

Frequency of exacerbations as a rate during follow-up was only reported in the RESPIRE, ORBIT and AIR-BX trials.15-17,23 Results of the meta-analysis are shown in figure 3. Inhaled antibiotics significantly reduced exacerbation frequency, rate ratio (RR) 0·81 (95% CI 0·67 – 0·97; p=0·02) with moderate heterogeneity, I2=52%. Excluding the AIR-BX studies, the effect estimate for the fluoroquinolones was RR 0·74 (95% CI 0·62 – 0·87; p=0·0005) with lesser heterogeneity, I2=34%. The number of patients experiencing at least one exacerbation was reported in 14 studies.15-17,21-23,25-27 The pooled data showed that inhaled antibiotics reduce exacerbations with a RR of 0·85 (95% CI 0·74 – 0·97; p=0·02), I2=49% (figure 3).

Time to first exacerbation was also only reported in an extractable format in the AIR-BX, ORBIT, RESPIRE and colistin studies.15-17,23 The pooled estimate showed that inhaled antibiotics prolonged the time to first exacerbation, hazard ratio 0·83 (95% CI 0·69 – 0.99; p=0·03), I2=44%. Frequency of severe exacerbations were studied in four trials and were significantly reduced by treatment, RR 0·43 (95% CI 0·24 – 0·78; p=0·005), I2=44%. These results were predominantly based on the ORBIT trials.17

Symptom endpoints

Two questionnaires, the Quality of Life Bronchiectasis (QOL-B) and the St Georges Respiratory Questionnaire (SGRQ), were used to evaluate respiratory symptoms and quality of life.30,31 The pooled results for each questionnaire are shown in figure 4.

Inhaled antibiotics were not associated with significant improvement in respiratory symptoms using the QOL-B questionnaire, mean difference (MD) 1·42 points (95% CI 0·21 – 3·04; p=0·09), with no heterogeneity, I2=1%. None of the eight studies showed an improvement above the proposed minimally important difference (MCID) of eight points compared with placebo.30 The difference between inhaled antibiotics and placebo in the SGRQ was also not statistically significantly in favour of the intervention but below the MCID of 4 points, MD -2·97 (95% CI -6·22 – 0·27; p=0·07), I2=68%.

Adverse effects

Treatment emergent adverse effects were reported in 13 studies.15-17,21-26 The overall rate of adverse events was not increased with inhaled antibiotic treatment, odds ratio (OR) 0·94 (95% CI 0·68 – 1·32; p=0·74), I2=56%. There was a trend towards a reduction in adverse events with fluoroquinolones, OR 0·73 (95% CI 0·50 – 1·05; p=0·09), I2=54%, n=1992, while adverse events were increased with aztreonam, OR 2·13 (95% CI 1·16 – 3·93; p=0·02), I2=0%, with limited data for other antibiotics. There was no increase in serious adverse events with inhaled antibiotic treatment, OR 0·88 (95% CI 0·66-1·17; p=0·37), I2=13%. In subgroup analyses the only significant increase was with aztreonam, OR 10·29 (95% CI 1·12 – 94·99; p=0·04), I2=8%. Adverse events leading to study drug discontinuation were similarly not significantly increased with inhaled antibiotics, OR 1·31 (95% CI 0·90 – 1·91; p=0.16), I2=35%, 16 trials (figure 5). Discontinuations were increased with aztreonam, OR 3·09 (95% CI 1·39 – 6·84; p=0·006), I2=38%, but not with aminoglycosides or fluoroquinolones.

Bronchospasm was reported in 69/1595 (4·5%) patients randomized to inhaled antibiotics and 65/1331 (4·9%) of placebo. The pooled OR was 0·91 (95% CI 0·64 – 1·29; p=0·39), I2=6%. Bronchospasm was significantly increased with aminoglycosides, OR 4·01 (95% CI 1·18 – 13·57; p=0·03), I2=0%, 3 trials. Surprisingly, bronchospasm was reported less frequently with fluoroquinolones than with placebo, OR 0·67 (95% CI 0·45 – 0·98; p=0·04), I2=0%.

Antibiotic resistance was consistently increased by treatment. Definitions of emergent resistance are provided in the online supplementary material (Table E4). The pooled risk ratio for isolation of a resistant organism was 2·04 (95% CI 1·55 – 2·67; p<0·00001) with heterogeneity (I2=42%), n=2536 with available data (15 studies). Resistance was not observed in the four studies of aminoglycosides20,24,25,27, RR 0·95 (95% CI 0·24 – 3·79; p=0·94), I2=32%, n=180, or in the single study of colistin26. Fluoroquinolones accounted for the majority of patients and the majority of evidence of resistance15-17, RR 1·92 (95% CI 1·45 – 2·56; p<0·00001), I2=45%, n=1993 (figure 5).

Other endpoints

We did not observe improvements in other efficacy endpoints with inhaled antibiotics. The relative change in FEV1 % predicted was a deterioration of 0·87% (95% CI -2·00 – 0·26%; p=0·13), I2=0%, eight trials. Absolute changes in FEV1 showed minimal change, MD 0ml (95% CI -30 – 30ml; p=0·81), I2=32%, eight trials. Six-minute walk distance was evaluated in three trials22,23 and was not improved with treatment, MD -1·4m (95% CI -12·7 – 9·6; p=0·81), I2=0%. Mortality was low across all trials, with deaths recorded in 25/1439 patients receiving inhaled antibiotics and 20/1232 receiving placebo. The pooled risk ratio was 1·05 (95% CI 0·57 – 1·92; p=0·87), I2=0%. Subjects demonstrating adequate adherence (typically defined as taking >80% of study medication) was 90·2% in the inhaled antibiotic groups and 90·0% in the placebo groups across 12 studies with 2436 participants. No heterogeneity was observed (I2=0%). Twenty-four hour sputum volume was evaluated in two studies26,27 and was not affected by inhaled antibiotic treatment, MD -2·6ml (95% CI -7·8 – 2·6ml; p=0·33), I2=0%.

Discussion

Our systematic review and meta-analysis of 16 randomized controlled trials of inhaled antibiotics in bronchiectasis, ranging from four weeks to 15 months, has demonstrated a statistically significant reduction in exacerbations with treatment, with consistent antimicrobial efficacy, but at the expense of an increase in antimicrobial resistance and a small decrement in lung function. Use of inhaled antibiotics was well tolerated in the populations studied with low rates of treatment emergent adverse effects or adverse effects leading to discontinuation of the study drug. There was an increase in antimicrobial resistance at the end of treatment, but this appeared to reduce after treatment was discontinued and there were no reports of treatment failure associated with resistance. Inhaled antibiotics did not improve symptoms or quality of life. The pooled data therefore suggest that inhaled antibiotics provide small but statistically significant benefits in terms of exacerbation reduction in the relatively broad patient populations in which they have been tested to date. The estimate of a 19% reduction in exacerbation rate and a 15% reduction in the number of patients experiencing at least one exacerbation may be regarded as clinically meaningful by many patients and clinicians in view of the important impact of exacerbations on quality of life, hospitalization risk and mortality.32 For others this benefit may not justify the burden of treatment and associated risks. The relative benefit observed with inhaled antibiotics in this meta-analysis is substantially lower than that reported for long-term macrolides, which demonstrated a 66% reduction in the proportion of patients experiencing one exacerbation in bronchiectasis and this may be important to take into account in future guidelines.33

Sputum bacterial load was consistently reduced with inhaled antibiotics. The majority of studies used a cycling regimen following a paradigm established in CF.34,35 With all antibiotic agents there was a rapid reduction in CFU/g during each treatment cycle followed by a rebound in CFU/g to near baseline levels within four weeks of treatment cessation.17,24,25 Despite this consistent antimicrobial efficacy, we did not observe a consistent relationship between antimicrobial effect and clinical benefits in terms of exacerbations or symptoms. Adverse events may have contributed to this inconsistent effect in some studies, such as the aztreonam studies;23 however, even studies without an excess of adverse effects demonstrated inconsistency. For example, in the ORBIT trials, the antimicrobial efficacy was equal between both ORBIT 3 and 4, but exacerbation results were inconsistent between the two trials.1717 This challenges the fundamental underlying principal for use of inhaled antibiotic treatment; bacterial infection is central to the vicious cycle of bronchiectasis and reducing bacterial loads should improve clinical outcomes.36,37 The inconsistent results from inhaled antibiotic studies suggest that the relationship between bacterial load, symptoms and outcomes in bronchiectasis may be more complex and that bacterial load is not directly linked to exacerbations and symptoms in all patients.

There were several design factors that may have contributed to heterogeneity of the results observed. Each trial protocol involved a different definition for protocol-defined exacerbations with some being more prescriptive than others.38 Some studies, the largest being AIR-BX, did not have a requirement for prior exacerbations in the previous year for inclusion in the study.25 In the majority of trials where previous exacerbations were reported, it was not stated how the prior exacerbations were defined. In several studies including the ORBIT, RESPIRE and colistin programmes, the placebo exacerbation rate was lower than expected based on prior exacerbation frequency.15–17 This may have resulted in a lower statistical power to detect differences. Other factors that may have affected exacerbation rates in the trials, in addition to the well-documented trial and placebo effects, could have been improved adherence to airway clearance and macrolide use.39–41 It is also notable that the placebo in most studies was nebulised saline, which has mucoactive properties, has been shown to improve quality of life and cough and is recommended as a therapy by the ERS guidelines.14,42,43 This may therefore not be a true placebo, which may limit the capability to observe differences in favour of an inhaled antibiotic. Developing alternative trial designs is beyond the scope of our study, but alternative approaches may include adding a third arm without intervention or comparing inhaled antibiotics, saline and an active comparator which is known to be effective such as long term macrolide.

P. aeruginosa infections in bronchiectasis have been associated with increased mortality, poorer quality of life and more frequent exacerbations.6,32 In this meta-analysis, there was no difference in outcomes with inhaled antibiotics between the studies that only included patients with chronic P. aeruginosa compared to studies with mixed bacteria. Similar results were obtained from sub-analyses of studies like RESPIRE, which included both P. aeruginosa and non-P. aeruginosa infected patients. Therefore the presence of P. aeruginosa infection does not appear to be sufficient to identify patients likely to respond to inhaled antibiotics.15,16 This supports the conclusion that patients with P. aeruginosa do not all require treatment with inhaled antibiotics and that future studies should focus on factors other than P. aeruginosa alone to enrich for responders. In the era of the lung microbiome it is increasingly inappropriate to believe that inhaled antibiotics target a single pathogen or that isolation of single organism by sputum culture can explain the heterogeneity of disease.1

The effect of inhaled antibiotics on quality of life measures was variable. The minimal clinically important difference was not achieved on either SGRQ or QOL-B in any of the studies, although statistically significant differences were observed in some individual studies.31,44 These results suggest that there may be patients who improve with treatment, but that “symptom responders” have not been identified. It is also possible that limitations of the available patient reported outcome measures, which have been little studied in bronchiectasis, also contribute to the null results.30,45 Few studies investigated sputum volume as an outcome and no impact of inhaled antibiotics was observed.

The patients receiving inhaled antibiotics experienced fewer adverse event rates compared to placebo. In particular, bronchospasm was rare except with use of aminoglycosides.12 Adverse events were increased with inhaled aztreonam, which may have been related to the patient population studied, which was not enriched for patients with a history of exacerbations and included a high percentage of patients with a history of COPD and non-tuberculous mycobacterial infection.25 The majority of safety data came from studies of inhaled fluoroquinolones, which did not appear to result in safety concerns. Advantages of the two ciprofloxacin formulations may include the liposomal and dry powder delivery methods, the intrinsic pharmacological properties of ciprofloxacin and potentially anti-inflammatory effects.17,24

The reported adherence in the trials we reviewed was high. With the exception of the placebo group in the Barker study, the minimum percentage of patients with adherence of at least 80% of the required doses was around 80%.27 It is likely that this was achieved through close monitoring and follow-up in optimal conditions.39 Despite this, the study by Haworth et al. did demonstrate a prolonged time to first exacerbation in adherent patients which was not evident in the overall population, suggesting that adherence may be a modifier of response.28

Resistance was evident at the end of treatment periods with nearly all antibiotics. In the trials with cyclical treatment regimens there was a trend towards higher MIC at the end of each treatment period, but the MIC reduced back to baseline at the end of the off-treatment periods. Longer-term continuous administration in the studies by Haworth of colistin and Murray of gentamicin did not have significant evidence of resistance.28,29 It is unclear if this reflects benefits of continuous treatment, differences between antibiotics or the microbiological methods used in the trials. Despite the apparent increase in microbial resistance, there is no evidence that increases in MIC result in clinically significant loss of treatment efficacy, as the concentrations of antibiotics delivered by the inhaled route will greatly exceed those achieved through systematic administration.

This meta-analysis has important limitations. Although we obtained a large amount of unpublished data, many endpoints had incomplete information because studies did not report data in a format that could be extracted and analysed. Trials designs were heterogeneous in terms of the endpoints used and the duration of studies. We therefore performed a random effects meta-analysis and have conducted a number of subgroup analyses to explore this heterogeneity, with results in all subgroups that support the overall conclusions of the study. Aetiology of bronchiectasis is an important potential cause of heterogeneity, but the majority of studies either enrolled exclusively populations with idiopathic or post-infective bronchiectasis15,16 or did not record aetiology at baseline17. This limitation should be addressed in future trials. Standardisation of design, outcome measures and analysis would help to improve future trials.38,46–48 There is now a consensus that exacerbation frequency is the most clinically relevant endpoint, and that a trial duration of 12 months allows sufficient time for an adequate number of events to occur while also removing seasonal influences and other potential confounders.48

Sixteen trials of inhaled antibiotics have now been conducted in bronchiectasis with broadly similar designs involving 2597 patients. Phase 2 trials tended to have bacterial load as the primary endpoint, while phase 3 studies have enrolled patients with bronchiectasis, chronic Gram-negative infection and a history of exacerbations in most cases. Studies have been largely unselective in terms of aetiology of bronchiectasis, severity of disease, lung function and concomitant therapy. For years it has been stated that further studies of inhaled antibiotics are required to bring the evidence base into line with that available in CF where inhaled antibiotics are the standard of care. However, the most recent Cochrane systematic review of inhaled antibiotics identified 18 trials with a total of 3042 participants with CF.11 There is therefore little difference, today, in the number of trials or number of participants investigated in trials of inhaled antimicrobials in the two diseases. We suggest that further trials of inhaled antibiotics in bronchiectasis that have similar inclusion criteria to those already conducted are likely to produce similar results to those reported here. Additional large trials of inhaled antibiotics are needed, but refinements to design are also required to produce more consistent and clinically relevant benefits. More trials are needed to test if continuous administration regimens would improve results. Enrichment for the “frequent exacerbator” phenotype by raising the inclusion criteria to a history of three or even four exacerbations per year is supported by the ORBIT 3 and 4 results, which found a reduction in exacerbation frequency with effect estimates much stronger than any observed in this meta-analysis when limited to the pre-specified group with frequent exacerbations.17 Finally, biomarkers of treatment response would be highly valuable to objectively identify responders. Bacterial load, sputum neutrophil elastase or parameters associated with the lung microbiome are amongst the most viable candidates studied to date.37,49,50

Conclusion

Inhaled antibiotics achieve a small but statistically significant reduction in exacerbations compared with placebo, but do not improve symptoms or quality of life. Antibiotic resistance is increased without resultant treatment failure, and compared to placebo, the adverse effect profile is favourable. Future studies should focus on identifying the optimal patient population to benefit from these treatments in bronchiectasis.

Conflicts of interest

Professor Chalmers reports grants and personal fees from Glaxosmithkline, Boehringer-Ingelheim, Astrazeneca, Pfizer, Bayer Healthcare, Grifols, Napp, Aradigm corporation, and Insmed outside the submitted work. The others authors declared no conflicts of interest.

Author contributions

Study design: IL, MLC, AS, JDC

Literature Search: MLC, JDC

Data collection: IL, MLC, JDC

Data analysis: JDC, IL, MLC, AS

Data interpretation: IL, MLC, AS, JDC

Quality assessment: IL, MLC, AS, JDC

Drafting the manuscript: IL, JDC

Revising the manuscript and approval for submission: IL, MLC, AS, JDC

References

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Tables

Study

Drug

Duration

N

Age (standard deviation)

F:M

FEV1 % predicted (standard deviation)

P. aeruginosa present/total population (percentage)

Other pathogens present/total population (percentage)

Primary outcome

Secondary outcomes

Wilson

Ciprofloxacin dry powder for inhalation 32·5mg vs placebo twice daily

84 days

60 vs 64

64·7 (11·8) vs 61·4 (11·9)

39:21 vs 43:21

57·2 (13·7) vs 54·6 (14·8)

32/60 (53·3) vs 35/64 (54·7)

H. influenzae 14/60 (23·3) vs 16/64 (25·0)

S. aureus 8/60 (13·3) vs 17/64 (26·6)

S. pneumoniae 7/60 (11·7) vs 2/64 (3·1)

M. catarrhalis 5/60 (8·3) vs 3/64 (4·7)

Effect of ciprofloxacin DPI on total bacterial density of pre-defined potential respiratory pathogens in sputum (CFU/g) after the 28 day treatment period

Time to exacerbation, emergence of new potential respiratory pathogens, emergence of resistance among baseline pathogens, changes in inflammatory biomarkers, change in 24hr sputum volume and colour, changes in FEV1, FVC and SGRQ, at days 29, 56 and 84, adverse events, results of physical examinations, vital signs and laboratory analyses

RESPIRE 1 – 14 days

Ciprofloxacin dry powder for inhalation 32·5mg vs placebo twice daily

12 months

137 vs 68

65·2 (13·5) vs 65·5 (12·9)

88:49 vs 44:24

59·42 (16·7) vs 57·37 (15·5)

83/137 (60·6) vs 41/68 (60·3)

At least 1 pre-specified 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, microbiological outcomes, QoL assessments (SGRQ and QOL-B), lung function

RESPIRE 1 – 28 days

141 vs 70

64·2 (12·1) vs 64·0 (13·5)

101:40 vs 52:18

59·48 (15·1) vs 61·7 (16·7)

83/141 (58·9) vs 45/70 (64·3)

RESPIRE 2 – 14 days

176 vs 88

60·4 (13·7) vs 60·4 (15·0)

96:80 vs 62:26

54·3 (17·3) vs 55·8 (18·6)

107/176 (60·8) vs 55/88 (62·5)

RESPIRE 2 – 28 days

171 vs 86

59·3 (14·2) vs 60·6 (13·7)

92:79 vs 52:34

56·4 (18·8) vs 56·2 (18·2)

99/171 (57·9) vs 54/86 (62·8)

ORBIT 2

Liposomal ciprofloxacin (liposome encased ciprofloxacin 135mg and free ciprofloxacin 54mg) vs placebo (empty liposomes in 0·9% saline) once daily

24 weeks

20 vs 22

70 (5·6) vs 59·5 (13·2)

10:10 vs 13:9

60·7 (24·1) vs 53·1 (22·7)

20/20 (100) vs 22/22 (100)

Other microorganisms present: Klebsiella (n=2) (intervention and placebo groups), Ochrobactrum anthropic (n=2) (placebo group only)

Mean change in sputum P. aeruginosa bacterial density (CFU/g) from baseline to end of first treatment cycle (28 days)

Time to first pulmonary exacerbation, FEV1, 6MWT, SGRQ, safety and tolerability

ORBIT 3

48 weeks

183 vs 95

64·3 (13·6) vs 66·7 (10·7)

127:56 vs 67:28

57·3 (21·9) vs 57·4 (20·2)

183/183 (100) vs 95/95 (100)

S. aureus 31/183 (16·9) vs 22/95 (23·2)

E. coli and coliforms 11/183 (6·0) vs 5/95 (5·3)

S. pneumoniae 5/183 (2·7) vs 3/95 (3·2)

H. influenzae 5/183 (2·7) vs 1/95 (1·1)

M. catarrhalis 2/183 (1·1) vs 0/95 (0)

Time to first pulmonary exacerbation

Number and frequency of pulmonary exacerbations, number of patients requiring IV antibiotics, QoL-B-RSS, change in P· aeruginosa bacterial density (CFU/g)

ORBIT 4

206 vs 98

63·3 (13·5) vs 64·2 (12·6)

134:72 vs 63:35

62·6 (22·2) vs 59·8 (20·8)

206/206 (100) vs 98/98 (100)

S. aureus 50/206 (24·3) vs 23/98 (23·5)

E. coli and coliforms 9/206 (4·4) vs 3/98 (3·1)

S. pneumoniae 10/206 (4·9) vs 3/98 (3·1)

H. influenzae 7/206 (3·4) vs 4/98 (4·1)

AIR-BX 1

Nebulised aztreonam 75mg vs placebo three times per day

28 weeks

134 vs 132

64·2 (12·9) vs 64·9 (12·1)

84:50 vs 97:35

60·4 (22·6) vs 64·5 (18·7)

112/134 (83·6) vs 105/132 (79·5)

History of mycobacterium 16/134 (11·9) vs 14/132 (10·6), no data for other organisms

Change in QOL-B-RSS from baseline to week 4

Change in QOL-B-RSS from baseline to week 12, time to first exacerbation by week 16, change in CFU/g, presence or absence of respiratory pathogens, changes in MIC of aztreonam

AIR-BX2

136 vs 138

63·3 (14·2) vs 62·7 (13·3)

89:47 vs 101:37

63·8 (19·5) vs 63·4 (21·6)

116/136 (85·3) vs 103/138 (74·6)

History of mycobacterium 8/136 (5·9) vs 12/138 (8·7), no data for other organisms

Drobnic

Nebulised tobramycin 300mg vs placebo (0·9% saline) twice daily crossover trial

13 months

10 vs 10

64·5 (38-75) (range)

No data

51·78 (16·5)

10/10 (100) vs 10/10 (100)

No data

Not specifically stated but presumed to be number of exacerbations

Number of hospital admissions, number of hospital admission days, antibiotic use, pulmonary function, SGRQ, tobramycin toxicity, density of P. aeruginosa in sputum, emergence of bacterial resistance, emergence of other opportunistic bacteria

Barker

Nebulised tobramycin 300mg vs placebo (1·25mg quinine in saline) twice daily

6 weeks

37 vs 37

66·6 (13·0) vs 63·2 (13·5)

23:14 vs 22:15

56·2 (21·2) vs 53·3 (22·1)

37/37 (100) vs 37/37 (100)

No data

Change in P. aeruginosa density (CFU/g) from baseline to week 4

Change in P. aeruginosa density from baseline to week 2 and to week 6, investigator’s subjective assessment of change in the patient’s general medical condition, percentage change in FEV1 and FVC % predicted, safety measurements

Orriols

Nebulised ceftazidime 1000mg and tobramycin 100mg twice daily vs standard care

12 months

7 vs 8

62·0 (8·5) vs 61·4 (10·3)

(SEM)

1:6 vs 4:4

62·3 (19·9) vs 56·2 (21·4)

(SEM)

7/7 (100) vs 8/8 (100)

No data

Not specifically stated but presumed to be number of hospital admissions

Number of hospitalization days, use of oral antibiotics, FVC, FEV1, PAO2, PACO2, drug toxicity, emergence of bacterial resistance

Murray

Nebulised gentamicin 80mg vs 0·9% saline twice daily

15 months

32 vs 33 randomized

27 vs 30 completed and included in analysis

58 (53-67) vs 64 (56-69) (median, interquartile range)

18:9 vs 15:15

72·9 (60-81·2 ) vs 63·4 (45·5-80·4) (median, interquartile range)

13/27 (48·1) vs 11/30 (36·7)

H. influenzae 11/27 (40·7) vs 15/30 (50·0)

S. aureus 2/27 (7·4) vs 1/30 (3·3)

S. pneumoniae 1/27 (3·7) vs 0/30 (0)

M. catarrhalis 0/27 (0) vs 2/30 (6·7)

Coliforms 0/27 (0) vs 1/30 (3·3)

Quantitative bacteriology in CFU/g

Sputum purulence and 24hr volume, pulmonary function tests, exercise capacity, LCQ and SGRQ, exacerbation frequency, inflammatory biomarkers

Haworth

Nebulised colistin 1 million international units vs placebo (0·45% saline) twice daily

26 weeks

73 vs 71

58·3 (15·3) vs 60·3 (15·8)

46:27 vs 37:34

55·9 (24·3) vs 57·6 (24·9)

73/73 (100) vs 71/71 (100)

H. influenzae 0/73 (0) vs 1/71 (1·4)

S. aureus 3/73 (4·1) vs 5/71 (7·0)

S. pneumoniae 2/73 (2·7) vs 0/71 (0)

S. maltophilia 0/73 (0) vs 0/71 (0)

M. catarrhalis 3/73 (4·1) vs 2/71 (2·8)

Time to exacerbation

Time to exacerbation (based on adherence recorded by the I-neb), severity of exacerbation, CFUs of P. aeruginosa, 24hr sputum weight, SGRQ, bronchoconstriction in 30 minuntes post first dose of study drug, FEV1, sensitivity of P. aeruginosa to colistin, CFUs of other potentially pathogenic organisms, adverse event reporting

TR02-107

Nebulised liposomal amikacin 280mg and 560mg vs placebo (empty liposomes in 1·5% saline) once daily

56 days

24 vs 19 vs 19

49·9(21·1) vs 58·5 (16·0) vs 49·4 (13·3)

10:14 vs 11:8 vs 9:10

64·5 (20·7) vs 71·4 (23·9) vs 62·6 (15·7)

24/24 (100) vs 19/19 (100) vs 19/19 (100)

No data

Safety of liposomal amikacin as measured by adverse event rates, change in oxygen saturations, change in FEV1

Frequency of cough with expectoration, PSSS, SGRQ, bacterial density of P. aeruginosa (CFU/g), pulmonary exacerbations

Table 1 Characteristics of the included studies. In each column data are presented with the active intervention first followed by data for the placebo or control group. Abbreviations: CFU/g, colony-forming units per gram; FEV1, forced expiratory volume in one second; FVC, forced vital capacity; SGRQ, St Georges Respiratory Questionnaire; QoL, quality of life; QOL-B, The Quality of Life Questionnaire-Bronchiectasis; 6MWT, six-minute walk test; IV, intravenous; RSS, The Respiratory Symptoms Domain Scale; SEM, standard error of the mean; PAO2, partial pressure of oxygen in alveoli; PACO2, partial pressure of carbon dioxide in alveoli; LCQ, Leicester Cough Questionnaire.

Figure legends

Figure 1. Flow chart of studies included in the meta-analysis. Abbreviations: NTM, non-tuberculous mycobacteria.

Figure 2. Forest plot showing the effect of inhaled antibiotic treatment on quantitative bacterial load in CFU/g of sputum. Effective estimates of individual studies are shown as squares with 95% CI indicated by lines. Pooled estimates for each subgroup and the total effect are shown as diamonds where the centre of the diamond is the pooled effect and the width of the diamond shows the 95% confidence intervals. The weight represents the percentage contribution of each study to the summary effect estimate. Abbreviations: CI, confidence intervals; df, degrees of freedom; IV, inverse variance.

Figure 3. A: Frequency of exacerbations and B: Number of participants experiencing at least one exacerbation. Effective estimates of individual studies are shown as squares with 95% CI indicated by lines. Pooled estimates for each subgroup and the total effect are shown as diamonds where the centre of the diamond is the pooled effect and the width of the diamond shows the 95% confidence intervals. The weight represents the percentage contribution of each study to the summary effect estimate. Abbreviations: CI, confidence intervals; df, degrees of freedom; IV, inverse variance.

Figure 4. Quality of life and symptom scales. A: Quality of life bronchiectasis questionnaire and B: St Georges Respiratory Questionniare. Please note that for both QOL-B and SGRQ a negative score has been shown as a reduction in symptoms for ease of interpretation. In the scales themselves a reduction in the scale indicates an improvement in symptoms with SGRQ but a worsening with QOL-B. Effective estimates of individual studies are shown as squares with 95% CI indicated by lines. Pooled estimates for each subgroup and the total effect are shown as diamonds where the centre of the diamond is the pooled effect and the width of the diamond shows the 95% confidence intervals. The weight represents the percentage contribution of each study to the summary effect estimate. Abbreviations: CI, confidence intervals; df, degrees of freedom; IV, inverse variance.

Figure 5. A: Adverse events leading to study drug discontinuation and B: Isolated bacteria with a minimum inhibitory concentration above the resistant breakpoint at the end of treatment. Effective estimates of individual studies are shown as squares with 95% CI indicated by lines. Pooled estimates for each subgroup and the total effect are shown as diamonds where the centre of the diamond is the pooled effect and the width of the diamond shows the 95% confidence intervals. The weight represents the percentage contribution of each study to the summary effect estimate. Abbreviations: CI, confidence intervals; df, degrees of freedom; IV, inverse variance.

1