Macrolides, mucoactive drugs and adherence for the management of bronchiectasis

From the authors:

We thank W-J. Guan and colleagues for their comments on the European Respiratory Society (ERS) guidelines for bronchiectasis [1]. We agree these are an important landmark for the field, and hope that clinicians, health professionals, patients and researchers will use the guidelines to improve the quality of care for bronchiectasis patients and to use the gaps identified to stimulate further research [1, 2].

We did not address the optimal duration of therapy with macrolides because there are no data to determine for how long patients should be treated [3–5]. Since the majority of high-quality evidence derived from studies of 6–12 months, a pragmatic approach is to undertake a trial of treatment for 6–12 months, discontinuing if it is ineffective [3–6]. Statements such as these cannot be included as formal recommendations within ERS guidelines presently because of the rigour of the GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. A PICO (patient, problem or population; intervention; comparison, control or comparator; and outcome) question, a systematic review and meta-analysis, and a grading of evidence are required to support specific statements in ERS guidelines. Until more evidence is available, there are insufficient data to make an evidence-based recommendation on macrolide duration [1].

Some of W-J. Guan and colleagues' statements are inaccurate. Macrolides were associated in one study with a change in microbiota composition using 16S ribosomal RNA (rRNA) PCR and sequencing, but this is not the same as indicating “an increased risk of harbouring macrolide-tolerant Pseudomonas aeruginosa”. Relative abundance by 16S rRNA sequencing is not the same as bacterial load and none of the individuals with an increase in relative abundance of P. aeruginosa in this study became culture positive for P. aeruginosa [7]. The significance of changes in the microbiome are currently unknown and results from small experimental studies need to be interpreted with care [7].

The statement that macrolides do not reduce exacerbation frequency in patients not infected with P. aeruginosa is also incorrect. This conclusion is based on a subgroup analysis of 41 participants in the BLESS trial, which did not achieve statistical significance [4]. In making our recommendation that macrolides should be used as first-line prophylactic antibiotic therapy for patients without P. aeruginosa infection, we considered the totality of evidence supporting macrolide use [1, 3–5]. Macrolides significantly reduced exacerbation frequency in both the EMBRACE and BAT trials in populations that had relatively few patients with P. aeruginosa [3, 5]. Our conclusions that macrolides reduce exacerbations in patients without P. aeruginosa infection and a history of exacerbations are based firmly on the available evidence [1].

We caution against extrapolating the results of the PEACE trial and similar studies in COPD to bronchiectasis. The extrapolation of results from studies in COPD and cystic fibrosis is problematic, as treatments such as recombinant human DNase and mannitol in cystic fibrosis and inhaled corticosteroids in COPD have not shown clear efficacy in bronchiectasis studies [1]. Mucolytics such as cysteine derivatives are widely used but we are unable to recommend them in an evidence-based guideline in the absence of trial data. W-J. Guan and colleagues suggest that these drugs may be used in patients not practicing airway clearance techniques. We disagree, and stand by our original evidence-based recommendation to use mucoactive drugs in patients practicing chest physiotherapy-based airway clearance [1]. While there is no evidence to support the use of cysteine derivatives, we found a number of small trials supporting the effectiveness of airway clearance [8, 9]. While further research in this area is needed, as a nonpharmacological intervention, the panel concluded that airway clearance should be the first-line intervention in bronchiectasis.

Finally, we agree that it is important to optimise adherence to all therapies in bronchiectasis. Patients with bronchiectasis often have multiple comorbidities and have to take large numbers of medications [10]. We agree that patients are more likely to adhere to therapies that are effective and so we would advocate following the evidence-based recommendations put forward in the ERS guidelines for management of adult bronchiectasis. Minimising medication burden in mild disease reduces the likelihood of nonadherence and, hence, we advocate prophylactic antibiotic therapies only for patients with frequent exacerbations (three or more per year) and only advocate the introduction of mucoactive drugs where simple measures have failed to control symptoms. Such a stepwise approach is consistent with the principals of optimising adherence ,and should be accompanied by patient education regarding the goals of therapy and the importance of treatment adherence.

Disclosures