2025+ERS临床实践指南：成人支气管扩张症的管理

Guideline methodology

The ERS guidelines for the management of bronchiectasis in adults were developed by an ERS Task Force in accordance with ERS rules for developing guidelines, which utilise the GRADE(Grading of Recommendations, Assessment, Development and Evaluation)approach. The Task Force was chaired by Professor James D. Chalmers(Dundee, UK) and Professor Stefano Aliberti(Milan, Italy). The Task Force was international, representing 13 countries across 4 continents. Participants were selected by the chairs based on their expertise and experience, and the task force was constituted according to ERS rules. The Task Force also included professional information specialists who supported the literature searches, three patient representatives from the European Multicentre Bronchiectasis Audit and Research Collaboration(EMBARC)-European Lung Foundation(ELF) patient advisory group with lived experience of bronchiectasis,23 and the ERS lead methodologist. Two members of the ERS guideline methodology network were assigned to the Task Force.Guideline development included virtual and face-to-face meetings, as well as extensive correspondence among voting panel members.

Questions and outcomes

The guideline includes 8 PICO (Patients, intervention, comparison, outcomes) questions and 3 narrative questions.24 For PICO questions, formal systematic literature searches, metaanalysis and grading were performed. For narrative questions, formal systematic literature searches were also completed. Evidence-to-decision (EtD) frameworks were used to generate evidence to decision tables for both PICO and narrative questions. For each question, relevant outcomes were selected by panel members and patient representatives based on their clinical judgement. Outcomes were then rated on a 9-point scale and classified as critical, important, or of limited importance through a panel vote.25 Only outcomes rated as critical or important based on the average panel score and subsequent discussion and consensus were included. Data for these outcomes were extracted for metaanalysis and considered in the evidence summaries.

Literature searches and systematic literature searches

Literature searches were designed by two independent information specialists in partnership with the chairs, the ERS methodologist, and a panel member experienced in methodology. Each question was supported by a systematic literature search of up to five databases (Pubmed, Embase, Web of Science Core Collection, Scopus and CENTRAL) and two clinical trial databases (Clinicaltrials.gov and ICTRP). Searches were performed from inception of the databases to between November 2023 and January 2024. (detailed search methodology is shown in the online supplement). All studies addressing the relevant question were considered, including randomized controlled trials (RCTs) and observational studies. Review articles (with the exception of existing systematic reviews), editorials, and other papers not containing original data were excluded. The study selection process for each question is presented in PRISMA flow charts in the supplement. Where RCTs addressing the question were identified, these were considered as the main body of evidence and analyses were limited to those studies. If no RCTs were identified, data from observational studies were extracted and considered as the main body of evidence.

We performed a search for all RCTs related to bronchiectasis (search terms presented in the online supplement). As no RCTs were identified addressing the PICO question on eradication, and limited data were identified for the PICO question on non-macrolide oral antibiotics, specific searches were performed for these two PICO questions (search terms are presented in the online supplement). The search strategy for Narrative question 1 and Narrative question 2 and 3 are also presented online. Data from studies that did not meet the criteria for inclusion in the evidence summaries could still be included in the ―additional considerations‖ section of the EtD framework, if they were relevant and informative to the discussions.

The first stage of literature review involved independent screening of titles and abstracts by two reviewers using Rayyan. Discrepancies in inclusion/exclusion were resolved by an independent third reviewer followed by discussion and consensus among all reviewers. Following full text review, based on predefined inclusion and exclusion criteria (see the online supplement), outcomes of interest were extracted using a pre-developed data extraction form in Microsoft excel, Meta-analyses were performed using Reviewer Manager version 5 (Cochrane). All meta-analyses used random effects models in view of the heterogeneity of patient populations, interventions and study designs identified. Risk of bias

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for RCTs was evaluated using the Cochrane risk-of-bias tool 2(RoB-2) for randomized trials embedded within the Review Manager software.

Certainty of evidence and strength of recommendations

The certainty of evidence for each outcome was evaluated using GRADE methodology as very low, low, moderate or high, taking into account risk of bias, inconsistency, indirectness,imprecision, and publication bias for each outcome.26 For imprecision, certainty of evidence was downgraded if the confidence intervals included the possibility of the lack of a clinically relevant effect using established minimum clinically important differences, where these are available27-30, and discussion among the panel members where this was not available.GRADE evidence profiles were created in GradePro for each PICO question and are presented in the supplementary material.

Recommendations

EtD frameworks were prepared for each question and discussed during a series of panel meetings. For the PICO questions and narrative question 1, evidence was reviewed and new recommendations formulated. For narrative questions 2 and 3 which deal with what is already recommended elsewhere, the panel reviewed existing recommendations from clinical guidelines and statements, identified those recommendations with which they agreed, and endorsed those recommendations. For all questions consensus was achieved by considering not only the available evidence, but also patients' values and preferences, as well as practical considerations.31 Formal voting was performed to agree the final recommendations, with a pre-specified threshold: 70% agreement was required to approve recommendations. Voting panel members declared their conflicts of interest and were disqualified from voting on recommendations where they declared a conflict. At least 50% of the panel had to be non-conflicted and eligible to vote for a valid recommendation in line with ERS rules. Recommendation meetings were held between July 2024 and January 2025. As recommendations were formulated within 12 months of the literature searches, the searches were not updated.

Recommendations are formulated as either strong or conditional. In line with GRADE terminology, we use“we recommend” for strong recommendations and“we suggest” for conditional recommendations.

Additional information to operationalize the recommendations is provided as remarks. The evidence supporting these remarks is discussed and reflects the clinical judgement of the guideline panel.

Summary of recommendations

|Question|Recommendation(s)|Remarks| |---|---|---| |NQ1- How can underlying causes of bronchiectasis be identified and how can the severity, and other treatable traits be|1. Management of patients with bronchiectasis should include standardized testing to identify the underlying cause of bronchiectasis, to evaluate disease severity and activity as well as risk of poor outcome,|See the relevant section for the associated detailed investigation and management considerations|

|evaluated?|and to identify co-morbidities and associated treatable traits (Strong recommendation for the intervention, moderate certainty of evidence stemming from narrative review of the evidence)|| |---|---|---| |PQ1- Should airway clearance techniques be used compared with no airway clearance techniques in adults with bronchiectasis?|2. We recommend that patients with bronchiectasis should be taught airway clearance techniques (strong recommendation for the intervention, very low certainty of evidence)|● Airway clearance techniques (ACTs) are best taught by a respiratory physiotherapy with appropriate experience. ● There is no evidence that one technique is superior to another and, therefore, treatment should be personalized. ● Airway clearance devices may be used to support manual ACTs. ● Previous ERS guidelines limited ACTs to patients with chronic productive cough. The current recommendation acknowledges that some patients with a dry cough, particularly those with mucus plugging on chest CT, may benefit from ACTs. Instruction in ACTs may also assist patients during periods of increased symptoms, such as exacerbations.| |PQ2- Should mucoactive drugs with no nucoactive drugs in adults with bronchiectasis?|3. We suggest to offer mucoactive treatments to patients with bronchiectasis where airway clearance has failed to control symptoms(conditional recommendation for the intervention, very low certainty of evidence) 4. We suggest not to offer recombinant DNA to patients with bronchiectasis(conditional recommendation against the intervention, very low certainty of evidence)|● The choice of mucoactive treatment should be guided by patient's co-morbidities and concerns around treatment burden and tolerability. Mucoactive treatments are best delivered as part of a comprehensive airway clearance regimen, which includes clearance instruction with or without devices, and regular physical exercise.| |PQ3- Should long term inhaled antibiotics be used compared with no inhaled antibiotics in adults with bronchiectasis?|5. We recommend to offer long- term inhaled antibiotics to patients at high risk of exacerbations and chronic infection with Pseudomonas aeruginosa despite standard care(Strong recommendation for the intervention, moderate certainty of evidence)|Patient at high risk of exacerbations include patients with a history of 2 or more exacerbations in the prior year OR 1 severe exacerbation OR 1 exacerbation plus severe daily symptoms. ● Inhaled antibiotics should be prescribed for a defined period and|

||6. We suggest to offer long-term inhaled antibiotics for patients at high risk of exacerbations and chronic infection with pathogens other than pseudomonas aeruginosa despite standard care (Conditional recommendation for the intervention, moderate certainty of evidence)|treatment response should be formally evaluated. If ineffective or poorly tolerated it should be discontinued ● Inhaled antibiotics are drug and device combinations and, therefore, patients should be provided with an appropriate nebulizer along with the medication. ● Many clinicians would perform a supervised test dose of inhaled antibiotics because of the risk of bronchospasm.| |---|---|---| |PQ4- Should long-term macrolides be used compared with no long- term macrolides in adults with bronchiectasis?|7. We recommend to offer long- term macrolides to patients at high risk of exacerbations despite standard care (Conditional recommendation for the intervention, moderate certainty of evidence)|● Macrolides are effective in a broad group of patients with bronchiectasis at high risk of exacerbations including patients with chronic P. aeruginosa infection, patients with airway infection caused by other pathogens, and those without evidence of airway infection. Macrolides should not be prescribed as monotherapy to patients with NTM infection. NTM should be excluded before initiating macrolide therapy. ● The most widely used long-term macrolide is azithromycin, typically at a dose of 250 mg daily or three times per week, or 500 mg three times per week. ● In view of the risk of adverse effects, patient education, baseline screening, and appropriate follow-up are important when prescribing macrolides.| |PQ5- Should long term non-macrolide oral antibiotic treatment be used compared with no long term oral antibiotic treatment in adults with bronchiectasis?|8. The panel suggests NOT to offer long-term non-macrolide oral antibiotics as a first line treatment to adult patients with bronchiectasis and a high risk of exacerbations(conditional recommendation against the intervention, very low certainty of evidence).|● Long-term non-macrolide oral antibiotics may have a role in specific situations where patients are at high risk of frequent exacerbations and other options such as long-term macrolides are contraindicated or have proven ineffective.| |PQ6- Should eradication treatment be used for patients with isolation of a new pathogenic|9. We suggest to offer eradication treatment to patients with a new isolation of Pseudomonas aeruginosa|● A new isolation of Pa aeruginosa may refer to the first time a patient has P. aeruginosa isolated or a further isolation following a prolonged period|

|microorganism compared with no eradication treatment?|(conditional recommendation for the intervention, very low certainty of evidence)|during which P. aeruginosa was not detected. Eradication practices vary both among panel members and globally. Some clinicians prescribe systemic antibiotics(e.g 2-week course) followed by a repeat sputum culture, discontinuing antibiotics if the sample is negative. Others would add inhaled antibiotics for 4 weeks to 3 months, without rechecking sputum cultures. The 2017 ERS guidelines provide examples of different antibiotic strategies.| |---|---|---| |PQ7- Should Long term inhaled corticosteroids be used compared to no long term inhaled corticosteroids in adults with bronchiectasis?|10.We suggest not to offer long term inhaled corticosteroids to patients with bronchiectasis where 0 do not have coexisting COPD or asthma(conditional recommendation against the intervention, low certainty of evidence)|● Patients with bronchiectasis should be evaluated for the presence of co- existing asthma and COPD. The presence of bronchictasis does not alter the recommendation to use inhaled corticosteroids(ICS) in patients with asthma or in a subset of patients with COPD. Suspected asthma or COPD should be appropriately investigated in patients with bronchiectasis. ● There is limited evidence suggesting that ICS may be beneficial in a subgroup of patients with bronchiectasis with elevated blood eosinophil counts who do not have asthma or other eosinophilic conditions. However, no recommendation on ICS use based on blood eosinophils is currently possible, and we recommend further research in this group. ● The use of ICS should be reevaluated in patients without a clear indication. Discontinuation of ICS may be appropriate in some patients.| |PQ8- Should pulmonary rehabilitation be used compared with no pulmonary rehabilitation in adults with bronchiectasis?|11.We recommend that patients with breathlessness and/or impaired exercise capacity should be offered pulmonary rehabilitation (strong recommendation for the intervention, very low certainty of evidence)|●The educational component of pulmonary rehabilitation(PR) should ideally be bronchiectasis specific and include discussion of airway clearance strategies. ● Patients with bronchiectasis should be encouraged to undertake regular physical activity, given its multiple|

|||health benefits.| |---|---|---| |NQ2- What diagnostic tests and interventions are recommended/used for managing exacerbations?|See relevant section for summary of 9 recommendations arising from narrative review of the evidence|See the relevant section for the associated detailed recommendations endorsed by the panel| |NQ3- What investigations and treatments are currently recommended in a patient with bronchiectasis who is rapidly deteriorating in terms of symptoms or exacerbations?|See relevant section for summary of 11 recommendations arising from narrative review of the evidence|See the relevant section for the associated detailed recommendations endorsed by the panel|

Table 1. Summary of recommendations in the 2025 ERS Bronchiectasis Guidelines.

Narrative question 1

How can underlying causes of bronchiectasis be identified, and how can severity,comorbidities, and other treatable traits be evaluated?

Recommendations

Management of patients with bronchiectasis should include standardized testing to identify the underlying cause of bronchiectasis, to evaluate disease severity and activity as well as risk of poor outcome, and to identify co-morbidities and associated treatable traits(Strong recommendation for the intervention, moderate certainty of evidence stemming from narrative review of the evidence)

Investigation and management considerations(the following is based on the evidence from systematic searches, panel discussions, the clinical experience and current practice of the panel and recommendations in other guidelines)

● All patients newly diagnosed with bronchiectasis should be screened for immunodeficiency by measurement of serum immunoglobulins(lgG, IgM, IgA), ABPA by measurement of total IgE, Aspergillus specific IgG and IgE, as well as blood eosinophils, and NTM by mycobacterial microscopy and culture.

● In patients at high risk of NTM infection based on clinical and radiological features a minimum of three sputum samples or a bronchoalveolar lavage should be obtained.

● Alpha-1 antitrypsin testing should not be performed routinely but should be considered in patients with suggestive clinical and radiological features such as basal emphysema or severe airflow obstruction.

● Patients with symptoms onset during childhood or with specific clinical or radiological features(independent of age of onset) should be screened for CF and PCD.

● Newly diagnosed patients with bronchiectasis should have a bronchiectasis severity index calculated to assess the risk of future complications(table

 Patients at higher risk of future complications should be identified. Such patients

should be considered for more frequent follow-up and a lower threshold for

treatment. High-risk groups include:

 Patients with COPD, PCD, or rheumatoid arthritis (RA)-associated bronchiectasis

 Patients with Pseudomonas aeruginosa or other enteric Gram-negative infections

 Patients with 2 or more exacerbations per year or 1 severe exacerbation (defined as requiring hospitalization or intravenous antibiotics) in the previous year

 Patients with severe symptoms including high volumes of daily sputum production and sputum purulence

 Patients with NTM infection

 Patients with ABPA

 Assessment of co-morbid illnesses should be part of the evaluation of all patients

with bronchiectasis:

 Patients at risk should be investigated for associated cardiovascular disease  Patients at risk should be investigated for associated osteoporosis

 Patients should be screened for symptoms of anxiety and depression and appropriate management initiated

 Rhinosinusitis and gastroesophageal reflux disease (GRD) are common comorbidities of bronchiectasis that should be identified and managed appropriately.

 Treatment burden and the impact on associated conditions should be considered as part of treatment decisions when managing bronchiectasis

 The assessments described here including considering the underlying cause, co-morbidities, disease activity and treatable traits, should be considered at all patient visits and not just at diagnosis.

Summary of evidence

Evidence supports standardized testing for underlying causes of bronchiectasis, as it may reveal treatable conditions, particularly immunodeficiency, NTM infection, ABPA, and CF.4,10,11,32–34 Identifying these conditions can significantly improve outcomes. Additionally, certain aetiologies, such as COPD, PCD, and RA, have treatment and prognostic implications and can influence follow-up and management strategies.35–38 Patients themselves often express a strong desire to understand the cause of their bronchiectasis, and this was supported by the patient representatives in the guideline panel.39 Identifying the underlying cause begins with a thorough history, including childhood history, reviewing HRCT findings, medications, pulmonary function tests, and supported by laboratory investigations. Resource implications exist for extensive testing, so the approach should balance benefit and cost. Therefore, testing for immunoglobulin deficiency, ABPA and NTM are reasonable as they are not prohibitively expensive, each are common (up to 10% depending on the series and even higher in certain populations) and they change management.10,40 Studies have found alpha-1 antitrypsin screening in unselected bronchiectasis patient populations to have a low positive rate41,42 and so routine screening is not recommended. Screening for rarer conditions like CF and PCD is important but carries significant cost and logistical challenges. The majority of patients with these genetic causes will have symptoms in childhood, but additional features that may suggest CF include upper

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lobe bronchiectasis, gastrointestinal symptoms (malabsorption/pancreatitic insufficiency/pancreatitis, intestinal obstruction), chronic rhinosinusitis with or without nasal polyps, male infertility and infection with S. aureus, P. aeruginosa or NTM. Although not all patients with bronchiectasis require screening for CF, a low threshold for testing should be adopted in view of the availability of specific CFTR modulator treatments.43–45 Diagnosis of PCD should follow the ERS/ATS guidelines.46 No cost-effectiveness data were identified in the analysed studies. Bronchiectasis aetiology varies globally, with post-TB bronchiectasis more common in Asia, Africa, and some parts of Europe47, CF is less prevalent in Asia, and ABPA is reported less common in Southern than Northern Europe.11

Bronchiectasis has a highly variable clinical course.48,49 Severity assessment aims at identifying patients at risk of progression, exacerbations, and mortality. The bronchiectasis severity index (BSI) is the most widely used standardised severity assessment tool, although others exist.48,50,51 Use of such tools may help to identify patients most likely to experience complications. Nonetheless, severity scores have limitations, and potential misclassification of patients could lead to under- or overtreatment; therefore, features such as frequent exacerbations38, severe daily symptoms52, P. aeruginosa infection53 and some aetiologies and associated conditions54 should guide clinicians toward more intensive monitoring and management.

The concept of severe daily symptoms and sputum purulence relies on clinical judgement and can be pragmatically defined as symptoms which have a severe impact on patients day to day functioning or quality of life.55 Objective tools such as the quality of life bronchiectasis questionnaire respiratory symptom score or St Georges Respiratory Questionnaire score may support identification of severe symptoms and the Murray colour chart can identify sputum purulence.27,56 In a recent study using the EMBARC registry is mean score in nearly 10,000 patients was QOL-RSS of 60 points and SGRQ >52 points.57 An objective sputum colour chart is available to identify sputum purulence.58

Comorbidities are frequently observed in patients with bronchiectasis and are associated with increased mortality and reduced quality of life.54 Cardiovascular diseases59, osteoporosis, depression, anxiety60, chronic rhinosinusitis61 and low body weight and malnutrition48 are common and have available treatment or preventive strategies that could yield desirable benefits.62

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 Figure 2. Investigation and management considerations for initial assessment and subsequent aetiological testing for adults with bronchiefasis. The central components(dark blue) are routine for all patients. This figure summarises the investigation and management considerations described above based on the systematic searches, panel discussions and current practices. These do not constitute separate recommendations. In a deteriorating bronchiefasis patient a comprehensive aetiological workup should be repeated and guided by clinical,radiological and demographic clues to identify any missed, evolving or newly relevant causes.

Justification of recommendation

The recommendation to test for underlying causes in bronchiectasis is justified by the potential benefits of identifying treatable conditions that can improve patient outcomes.Although such testing may increase healthcare costs and introduce diagnostic complexity,the prioritisation of diagnosing treatable etiologies outweighs these concerns.The recommendation to limit testing for alpha-1 antitrypsin deficiency(A1ATD), CF and PCD to patients with suggestive clinical features reflects a targeted diagnostic approach that balances the need for comprehensive evaluation while minimizing unnecessary testing,healthcare costs and patient burden.

Assessing disease severity is essential to ensure a standardised evaluation of bronchiectasis, facilitating appropriate management strategies. Additionally, the identification and management of comorbidities support a holistic approach to patient care, ultimately improving clinical outcomes.

The treatable traits concept emphasizes the importance of a personalized approach to bronchiectasis management. Effective treatment strategies targeting the underlying cause, associated co-morbidities, and key disease features (infection, impaired mucociliary clearance, inflammation, etc) depend on comprehensive patient assessment to identify treatable traits.

Implementation considerations

Implementing testing for underlying causes in bronchiectasis requires a structured approach to address several practical challenges, including regional disparities in diagnostic capacity, variability in disease aetiology across populations, and the lack of standardized follow-up and management protocols. Testing for certain underlying causes (particularly PCD) may be difficult to implement in many regions due to limited access to specialized diagnostic facilities. While evidence exists to support treatment of some treatable traits (e.g cardiovascular disease secondary prevention), other areas lack clear therapeutic data. It is important to note that the screening strategies described here are considered first-line investigations. In patients with strong clinical suspicion of a particular condition, additional testing may be appropriate. An example of this is immunodeficiency. For example, although low immunoglobulin levels and functional antibody testing (e.g measurement of pneumococcal antibody followed by pneumococcal vaccination if low and repeat antibody measurement 6 weeks later) can identify many immunodeficiencies, referral to an immunologist should be considered for patients with suggestive features, even when initial immunoglobulin levels are normal.

Monitoring/evaluation

Etiological testing is typically undertaken at the time of diagnosis; however, this should be viewed as an ongoing process. If patients‘ clinical features change in a way that raises suspicion for a new diagnosis, further testing should be undertaken. Although formal severity assessment is recommended at diagnosis, it should not be limited to that time point. Assessment of future risk should be a key part of every clinical review.

Future research

Large-scale studies performing genetic testing for PCD, CF and primary immunodeficiecies in adults with bronchiectasis, with appropriate downstream testing to confirm the diagnoses, are required to determine the true prevalence of these conditions and to inform the development of optimal screening strategies. Studies implementing comprehensive aetiological testing approaches across different regions/countries are required to determine if the recommended screening strategies are globally applicable and cost-effective.

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|Severity marker|Score| |---|---| |Age, yrs|| |<50|0| |50-69|2| |70-79|4| |80+|6| |BMI, kg/m2|| |<18.5|2| |18.5-25|0| |26-29|0| |30 or more|0| |FEV1, % predicted|| |>80|0| |50-80|1| |30-49|2| |<30|3| |Previous hospital admission|| |No|0| |Yes|5|

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|Severity marker|Score| |---|---| |Number of exacerbations in previous year|| |0|0| |1-2|0| |3 or more|2| |MRC breathlessness score|| |1-3|0| |4|2| |5|3| |Pseudomonas colonization|| |No|0| |Yes|3| |Colonization with other organisms|| |No|0| |Yes|1| |Radiological severity:≥3 lobes involved or cystic bronchiectasis|| |≥3 lobes involved or cystic bronchiectasis|1| |<3 lobes involved|0|

Table 2. The Bronchiectasis Severity Index. Patients receive a score out of a maximum of 24 points. 0-4 points is considered "mild"/low risk of mortality of hospitalization, 5-8 points is considered moderate or intermediate risk of mortality and hospitalization. $\geq 9$ points is considered severe or high risk of mortality and hospitalization.

PICO QUESTION 1- AIRWAY CLEARANCE

Should airway clearance techniques be used (compared to no airway clearance techniques) in adults with bronchiectasis?

Recommendation

We recommend that patients with bronchiectasis should be taught airway clearance techniques (strong recommendation for the intervention, very low certainty of evidence)

Remarks

 Airway clearance techniques (ACTs) are best taught by a respiratory physiotherapy

with appropriate experience.

 There is no evidence that one technique is superior to another and, therefore,

treatment should be personalized.

 Airway clearance devices may be used to support manual ACTs.

 Previous ERS guidelines limited ACTs to patients with chronic productive cough. The

current recommendation acknowledges that some patients with a dry cough,

particularly those with mucus plugging on chest CT, may benefit from ACTs.

Instruction in ACTs may also assist patients during periods of increased symptoms,

such as exacerbations.

Summary of evidence

We included two RCTs (a 12-month RCT and a 3-month cross-over trial) that evaluated ACTs in 39 participants versus 40 receiving standard care or placebo exercises. These studies showed no significant difference overall in the percentage of participants with at least one exacerbation during follow-up (OR 0.58, 95% CI 0.21 – 1.58)63,64, whilst the 12-month RCT by Munoz et al. showed a significant reduction in exacerbation rate over 12 months. Improvements in health related quality of life were clearly demonstrated with ACTs, with a statistically significant mean total Leicester Cough Questionnaire (LCQ) score improvement of 2.81 (95% CI 0.72 – 4.9) and a mean difference in St. George‘s Respiratory Questionnaire (SGRQ) score of -12.51 points (95% CI -22.39 – -2.62).63,64 Both of these exceed the reported minimum clinically important difference (MCID) for these measures. Our metaanalysis also indicated a significant reduction in breathlessness with a mean difference in the modified medical research council (mMRC) dyspnoea scale of -1.36 points (95% CI -2.14 – -0.58) and significant increase in 24-hour sputum volume (MD 6.2 ml, 95% CI 0.46 –

11.95).

The overall certainty of evidence was rated as very low, primarily due to a high risk of bias, imprecision. No studies reported on hospitalisation rates, adverse effects, or treatment burden.

Justification of recommendations

ACTs are associated with improved quality of life and symptoms, and may reduce exacerbations.63,64 Airway clearance is a key component of daily bronchiectasis management.65 Despite the very low certainty of evidence, the panel issued a strong

recommendation based on the following: i) ACTs are self-administered, low-cost, and

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accessible; ii) Patients widely recognise their benefits; iii) The recommendation was strongly supported by patient representatives. Although adverse effects and harms were not systematically reported or collected, ACTs are widely believed to be safe and low risk of adverse events. These factors outweigh the limitations of the evidence base and highlight a need for broader implementation. Airway clearance is underutilized in clinical practice, and this recommendation should encourage increased uptake among healthcare professionals and policy.66

Implementation considerations

Patients should receive appropriate training and personalised guidance in selecting the most suitable ACTs for their individual needs by a specialist respiratory physiotherapist. It is acknowledged that not all patients will have access to a respiratory physiotherapist and other healthcare professionals may be involved in teaching airway clearance. Although direct comparative studies are lacking, clinical experience from the panel members suggest starting treatment with independent ACTs (defined as methods used to clear mucus and secretions from the airways that can be performed by an individual without the need for assistance from another person or specialized equipment). Adjuvant airway clearance devices may be considered to enhance sputum properties, facilitate consistent treatment, and increase adherence and tolerability.65 These devices may not be equally accessible in low- and middle-income settings, and patients typically bear the costs due to limited coverage by health systems. Although the acceptability of remote delivery for this intervention is uncertain, it may offer an opportunity to enhance accessibility. Additionally, the panel supports implementing ACTs alongside an educational approach that identifies the benefits of this intervention and addresses barriers and facilitators to promote long-term adherence.67 Finally, when inhaled mucoactive agents or bronchodilators are administered alongside ACTs, the timing of administration in relation to ACTs should be carefully managed to maximize treatment synergy.

There are no head-to-head studies comparing different ACTs, and the consensus is that no one technique is superior to others.18,65 Therefore, techniques should be chosen based on individual preference and effectiveness.

Monitoring/evaluation

Patients trained in ACTs should be periodically reviewed to ensure the techniques are still performed correctly, are suitable to patient needs and/or to modify techniques if the disease changes.

Future research

Large RCTs of ACTs in bronchiectasis would be desirable, though controlled trials of ACTs are complex since ACT are standard of care and there are ethical considerations in withholding this treatment. Key research priorities in this area include: i) Long-term impact of ACTs on exacerbation frequency (e.g 12 months or greater); ii) Optimal strategies for delivering ACT training; iii) Effectiveness of virtual methods such as online training or video/remote training to deliver ACTs; iv) Additional benefits provided by airway clearance devices; v) Whether exercise alone is as effective as ACTs in improving respiratory symptoms, and whether patients performing regular exercise also require ACTs68; vi) The

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role, effectiveness, and adaptability of ACTs during exacerbations, especially in relation to exacerbation severity and individual patient characteristics.

PICO QUESTION 2 - Mucoactive drugs

Should mucoactive drugs be used (compared with no mucoactive drugs) in adults with bronchiectasis?

Recommendation

We suggest to offer mucoactive treatments to patients with bronchiectasis where airway clearance has failed to control symptoms (conditional recommendation for the intervention, very low certainty of evidence)

We suggest not to offer recombinant DNAse to patients with bronchiectasis (conditional recommendation against the intervention, very low certainty of evidence)

Remarks

 The choice of mucoactive treatment should be guided by patient‘s co-morbidities and

concerns around treatment burden and tolerability.

 Mucoactive treatments are best delivered as part of a comprehensive airway

clearance regimen, which includes personalized airway clearance instruction with or

without devices, and regular physical exercise.

Summary of evidence

We included nine randomised trials investigating mucoactive treatments, including 12-52 weeks of inhaled mannitol69,70, 15 days of oral erdosteine71, 2-24 weeks of aerosolised recombinant human DNAse I72,73, 3-12 months of inhaled hypertonic saline (6% or 7%)74–76, and 12 months of oral N-acetylcysteine77. In three randomised trials, testing mannitol, hypertonic saline and N-acetylcysteine, we found no significant difference overall in exacerbation frequency (MD -0.28, 95% CI -0.63 – 0.07). We found no difference in exacerbation frequency rate ratio (0.99, 95% CI 0.80 – 1.23) from 2 trials and no difference in the proportion of patients free of exacerbations during follow up (odds ratio [OR] 1.48, 95% CI 0.88 – 2.51) from 3 trials.77–79 One study reported time to first exacerbation that was significantly prolonged with 400 mg inhaled mannitol compared with low-dose mannitol control twice daily for 52 weeks (hazard ratio [HR] 0.78, 95% CI 0.63 – 0.96).69 There were no differences found in the odds of participants remaining free from hospitalisation during follow-up (OR 3.35, 95% CI 0.32 – 35.36). Regarding quality-of-life measurements, in three studies overall there was a two point improvement in total SGRQ with treatment (MD -2, 95% CI -3.6 – -0.4) and in one study a large improvement in the quality of life bronchiectasis respiratory symptom domain was observed MD 11.42 lower (20.38 lower to 2.46 lower)]. In one trial of 12-months of N-acetylcysteine, 24 hour sputum volume was significantly lower, with a mean difference of 11.82 ml (95% CI -19.31 – -4.33) between the treatment and placebo groups.77 Across four studies, we found no significant differences in percentage of participants experiencing at least one adverse event related to study medication in the

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treatment groups (OR 1.4, 95% CI 0.96 – 2.04). No studies reported on impact on activities of daily living.

Justification of recommendation

Mucus in bronchiectasis is typically hyperconcentrated and viscous, impairing mucociliary clearance.80 Mucus plugging, a common radiological feature, is associated with exacerbation risk and disease severity.15 Oral mucoactive agents, such as carbocisteine or Nacetylcysteine, reduce mucus viscosity though evidence is limited.12 Nebulized hypertonic saline and inhaled mannitol hydrate mucus and stimulate cough to facilitate clearance. Mucoactive treatments may improve symptom burden and quality of life when used in addition to airway clearance and exercise. Despite limited evidence our recommendation prioritises improvements in quality of life and symptoms, and is supported by the lack of significantly increased adverse events. One study assessing inhaled mannitol suggests greater benefit in patients with more severe symptoms.52 Highly symptomatic patients with poor quality of life could therefore be considered for mucoactive treatment. Inhaled mucoactive treatments may cause wheezing or bronchospasm. The use of pre-treatment bronchodilators can mitigate this risk. Notably, recombinant human DNase was ineffective and reduced FEV1 in a previous trial. Therefore, its use is not recommended.73

Implementation considerations

An individualized approach should be adopted, taking into account symptom and treatment burden, feasibility, tolerability, and patient preferences. As nebulized hypertonic saline can cause bronchospasm, a test dose and pre-treatment with a bronchodilator, especially in patients with asthma or severe airflow limitation, are recommended. Issues related to device availability, cleaning requirements, and replacement costs may increase treatment burden of inhaled therapies, as emphasized by patient representatives among the Task Force.81 In this regard, high-efficiency, easy-to-clean nebulizers may be advantageous in resource-rich setting, Importantly, ACTs should be introduced before mucoactive therapy to ensure maximum treatment effectiveness.65

Monitoring/evaluation

Mucoactive treatments are primarily prescribed to improve symptoms and quality of life. If no clinical benefit is evident after a reasonable trial period (e.g 3 months), treatment should be discontinued.

Future research

Large RCTs using precision medicine approaches to target mucoactive treatments based onsymptom burden and/or particular sputum characteristics (i.e abnormal mucins, mucus properties or DNA content) are needed. Although recombinant human DNase proved ineffective in a trial published in 199873, new insights into neutrophil extracellular traps and poor disease outcomes82, as well as bronchiectasis endotypes83, suggest that further research is needed to clarify whether specific subgroups of adults with bronchiectasis may

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benefit from recombinant human DNase. Mucociliary clearance targeting treatments, in contrast to antibiotics and anti-inflammatory treatments, have been neglected and the development of novel mucoactive agents should be a research priority in future.

PICO QUESTION 3 - Inhaled antibiotics

Should long term inhaled antibiotics be used (compared with no long term inhaled antibiotics) in adults with bronchiectasis?

Recommendation

We recommend to offer long term inhaled antibiotics to patients at high risk of exacerbations and chronic infection with Pseudomonas aeruginosa despite standard care (Strong recommendation for the intervention, moderate certainty of evidence)

We suggest to offer long term inhaled antibiotics to patients at high risk of exacerbations and chronic infection with pathogens other than Pseudomonas aeruginosa despite standard care (Conditional recommendation for the intervention, moderate certainty of evidence)

Remarks

 Patient at high risk of exacerbations include patients with a history of 2 or more exacerbations in the prior year OR 1 severe exacerbation OR 1 exacerbation plus severe daily symptoms.

 Inhaled antibiotics should be prescribed for a defined period and treatment response should be formally evaluated. If ineffective or poorly tolerated it should be discontinued

 Inhaled antibiotics are drug and device combinations and, therefore, patients should be provided with an appropriate nebulizer along with the medication.

 Many clinicians would perform a supervised test dose of inhaled antibiotics because of the risk of bronchospasm.

Summary of evidence

We included 18 randomised trials for this question, noting that some manuscripts reported more than one trial within a single paper. Across 13 trials, inhaled antibiotics reduced exacerbation frequency by 20% compared to controls (rate ratio 0.80, 95% CI 0.70-0.92).20,84–90 Across 18 studies, there was a significant 15% reduction in the number of patients with at least one exacerbation (risk ratio 0.85, 95% CI 0.76 – 0.94) 20,84,93–95,85–92, frequency of severe exacerbations was reduced by 43% in eight studies (rate ratio 0.57, 95% CI 0.35-0.94)20,84,86,94,96,97, and time to first exacerbation was prolonged in pooled data from 14 studies (hazard ratio [HR] 0.81, 95% CI 0.71-0.93) in those receiving inhaled antibiotics. Regarding quality of life and symptoms, there was no significant improvement in QoL-B respiratory symptoms score (MD 2.14, 95% CI 0.28 – 4.57)84–90 or total SGRQ score (MD 2.63, 95% CI -5.37 – 0.1)20,87,88,93–96 with inhaled antibiotic treatment overall in 11 and eight studies, respectively. In 18 studies, an increase in antimicrobial resistance was found with a 1.96-fold higher risk of identifying bacterial isolates with antibiotic minimum inhibitory concentrations (MICs) indicative of resistance in those receiving antibiotics (RR 1.96, 95%

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CI 1.55 – 2.48). There were no differences in numbers of participants reporting treatmentemergent adverse events (TEAEs) in 15 studies (OR 1.04, 95% CI 0.81 – 1.35)20,84,95,96,85–88,90,91,93,94 and no differences in all-cause mortality (OR 1.04, 95% CI 0.57 – 1.89) from 15 studies.

The certainty of evidence was rated as moderate overall. The majority evidence comes from studies included patients infected with P. aeruginosa while evidence for patients without P. aeruginosa infection remains more limited.

Justification of recommendation:

A strong recommendation was made for patients chronically infected with P. aeruginosa, based on clinically relevant reduction in exacerbation frequency, including severe exacerbations. A conditional recommendation was made for patients with other chronic infections, given the predominance of P. aeruginosa in the available meta-analysis and the availability of effective treatments, including long term macrolides, in these patients. The recommendation prioritises the clinically relevant improvements in exacerbation outcomes, in the context of the poor outcomes experienced by patients with chronic P. aeruginosa infection, and is also informed by the lack of any significant increase in adverse events. The panel acknowledged the risk of antimicrobial resistance which is important at population level but is of uncertain significance for the individual patient in the context of inhaled antibiotics. Feedback from patients also supported a strong recommendation.

Previous guidelines recommended the use of long-term treatments such as inhaled antibiotics for patients with 3 or more exacerbations per year.18 The current wording of the recommendation reflects the understanding that the number of exacerbations in the previous year is an important risk factor for future exacerbations but is not the only risk factor.38,47,48,52,98 Patients with a high burden of daily symptoms are also at high risk of future exacerbations, and the threshold to commence long-term treatments may be lower in patients with other important prognostic features.52,57 Clinical features associated with a higher risk of future exacerbations include P. aeruginosa infection, PCD, COPD, RA and sputum purulence.35,36,53,58,99 The present recommendation, therefore, suggests that patients with 2 or more exacerbations are likely to be at high risk of future exacerbations, but that some patients with a lower number of exacerbations with a high symptom burden may also benefit from preventative treatment. The threshold to commence treatment should be individualised taking into account the key risk factors in each individual patient as well as considerations around the balance of risks and benefits, availability, cost and the burden of treatment.

Antimicrobial stewardship is a key consideration. Long-term antibiotic treatment should be used after other aspects of treatment have been optimised and, therefore, other options such as airway clearance, vaccination against respiratory pathogens, treatment of underlying causes and co-morbidities have been addressed.

Practical considerations:

Inhaled antibiotic treatments have historically been given one month on and one month off by some clinicians. There is some evidence that continuous use of antibiotics provides sustained symptomatic benefit compared to cyclical treatment and no evidence that resistance is different.20,84,100,101 Some clinicians advocate continuous use of antibiotics on this basis but availability and cost considerations may also influence this.

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Treatment burden is an important consideration for patients prescribed inhaled antibiotics, particularly in relation to administration time and cleaning of equipment, which may affect adherence.102 In line with antimicrobial stewardship principles inhaled antibiotics should be used where other measures have been ineffective to prevent exacerbations. There should be clear evidence of chronic bacterial infection of the airways and that other potential drivers of frequent exacerbations have been considered and addressed. Other important practical considerations are included in the remarks above. In addition to be provided with an appropriate nebulizer patients and/or caregivers should be appropriately trained in their use and cleaning. Inhaled antibiotics are often taken alongside with other medications. The recommended sequence of treatments, as described in the 2017 ERS bronchiectasis guidelines, would be to take bronchodilators first, followed by nebulized/inhaled mucoactive drugs, followed by performing airway clearance, and then taking inhaled antibiotics to optimise deposition.18

Monitoring and evaluation

Treatment should be prescribed for a defined period and re-evaluated. If no clear benefit is observed, inhaled antibiotics should be discontinued, and alternative strategies should be considered to reduce exacerbations. If benefit is observed treatment may be continued with monitoring for adverse effects. Long term treatment is defined as a minimum of 3 months but most available data is over 12 months. The optimal period for evaluating response is not known, but as the primary benefit is on exacerbations many clinicians would re-evaluate efficacy after 1 year.

Research priorities

Although long term inhaled antibiotics show efficacy in studies, predicting individual response remains a challenge as reflected by inconsistent results across RCTs. The panel, therefore, recommends studies that should focus on precision approaches to optimize treatment selection. Key research questions include: i) Can inflammatory or microbial biomarkers predict patients‘ response to inhaled antibiotics?; ii) What is the best way of identifying patients at risk of future exacerbations? Iii) What is the impact of inhaled antibiotics on antimicrobial resistance and what, if any, are the clinical consequences of resistance on treatment efficacy and future outcomes.

PICO QUESTION 4 – Macrolides

Should long-term macrolides be used (compared with no long-term macrolides) in adults with bronchiectasis?

Recommendation

We recommend to offer long-term macrolides to patients at high risk of exacerbations despite standard care (Strong recommendation for the intervention, moderate certainty of evidence)

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Remarks

 Macrolides are effective in a broad group of patients with bronchiectasis at high risk

of exacerbations including patients with chronic P. aeruginosa infection, patients with

airway infection caused by other pathogens, and those without evidence of airway

infection.

 Macrolides should not be prescribed as monotherapy to patients with NTM infection.

NTM infection should be excluded before initiating macrolide therapy.

 The most widely used long-term macrolide is azithromycin, typically at a dose of 250

mg daily or three times per week, or 500 mg three times per week.

 In view of the risk of adverse effects, patient education, baseline screening, and

appropriate follow-up are important when prescribing macrolides.

Summary of evidence

We included 9 randomized controlled trials. Meta-analysis found a significant and highly clinically relevant 52% reduction in exacerbation frequency/rate (HR 0.48, 95% CI 0.37 –

0.62) in those receiving macrolides compared with those who did not from four randomized trials.103–107 In five randomised trials, a significant 36% lower risk of having exacerbations (risk ratio 0.64, 95% CI 0.46 – 0.89) was found 103–106,108,109, Two trials reported a significantly longer time to first exacerbation (HR 0.32, 95% CI 0.21 – 0.47)104,105. A clinically-meaningful, significant improvement in SGRQ total score was found in seven studies, with average improvement of 7.26 points (MD -7.26, 95% CI -10.94 – -3.59)103–105,107,109–111 in participants receiving long term macrolides versus those in the comparator groups. There were no differences in the frequency of identification of antimicrobial resistant organisms between participant groups across two studies (OR 1.08, 95% CI 0.22 – 5.19) or in the odds of isolating a new pathogen (OR 0.82, 95% CI 0.41 – 1.63) within two trials. In data from six studies, there was no significant increase in adverse events in those receiving macrolides (OR 0.86, 95% CI 0.53 – 1.39).103–105,108,110,111 In three smaller studies, reported mortality overall was low, with no differences between groups and one study also reported no differences in incidence of hospitalisation (OR 0.45, 95% CI 0.04 – 5.19).

Justification of recommendations

A strong recommendation is supported by a highly clinically relevant reduction in exacerbations and a highly meaningful improvement in quality of life with long-term macrolide treatment.106 The trials show no major safety concerns, and in studies of 6 to 12 months duration, antimicrobial resistance was not identified as a significant issue. The largest studies included patients with at least 1 exacerbation per year, and benefit was demonstrated across multiple patient subgroups including those with low exacerbation frequency and the subgroup of patients with P. aeruginosa infection.106

While previous guidelines recommended the use of long-term treatments such as macrolides for patients with 3 or more exacerbations per year18, the current wording of the recommendation reflects the recognition that past exacerbation frequency is a key, but not exclusive, predictor of future risk.38,47,48,52,98 Patients with a high burden of daily symptoms are also at high risk of future exacerbations, and, in such cases, the threshold for initiating long-term treatments may be lower.52,57 Clinical features associated with a higher risk of future exacerbations include P. aeruginosa infection, PCD, COPD, RA and sputum purulence.35,36,53,58,99 The present recommendation therefore suggests that patients with >=2 exacerbations are likely to be at high risk of future exacerbations, but that some patients with

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a lower number of exacerbations with a high symptom burden or other risk factors may also benefit from preventative treatment. The threshold to commence treatment should be individualised, based on patient-specific risk factors, risk-benefit balance, and treatment burden.

Practical considerations

Although no major safety concerns were identified in the trials, macrolides are not without risks and most studies carefully excluded patients at high risk of macrolide related adverse events.103–105 Prior to starting macrolide maintenance therapy, patients should be screened for NTM infection, QT-time abnormalities, and liver/kidney function abnormalities.112 Patients should be warned about the possibility of ototoxicity, which usually manifest as tinnitus, hearing loss and vestibular dysfunction. Treatment should be discontinued if these symptoms occur. Many clinicians will perform ECG, urea and electrolytes and LFTs 2-3 weeks after initiation of macrolide maintenance treatment to monitor QT interval and liver/ kidney function. However, the optimal monitoring strategy is not yet defined due to a lack of studies.

The optimal macrolide dosage has not been established. The largest trials used either azithromycin 250 mg daily or 500 mg three times per week, or erythromycin.103–105 The observed efficacy of erythromycin suggests a class effect, although azithromycin is preferred due to better tolerability and the possibility of intermittent dosing.12 Adverse effects appear larger in studies that use higher doses104,113 and clinicians may consider starting at the lowest effective dose (e.g azithromycin 250 mg daily or three times per week, or 500 mg three times per week).112

Monitoring and evaluation

Patients on long term macrolide therapy should be reviewed on an individualized basis to assess efficacy (e.g. number of exacerbations, symptoms) and side effects. The optimal duration of macrolide therapy is unknown, with the longest studies being up to 12 months. Discontinuation may be considered after one year if no clear benefit is observed, or, alternatively, if remission of exacerbations and symptoms is reached. In such cases, a careful discussion about the risks and benefits of discontinuation is needed due to the risk of relapse.

Research priorities

Key research questions in the field of long-term macrolide use include: i) What is the longterm safety profile of macrolides beyond 12 months, including impacts on antimicrobial resistance, emergence of new pathogens, and adverse effects?; ii) Can macrolide treatment prescribed at early disease stage (e.g mild bronchiectasis with non-frequent exacerbations but risk-factors for progression) result in slowing disease progression or even in achieving remission?; iii) What is the optimal monitoring strategy for adverse events? Do all patients require ECGs before and after macrolide initiation? Is NTM screening required for all patients or only for patients with high-risk clinical features? What is the value of baseline or follow-up audiology screening?; iv) Can macrolides be safely discontinued in clinically stable patients with a low symptom and exacerbation burden?

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PICO QUESTION 5- Oral antibiotics

Should long-term non-macrolide oral antibiotics be used (compared to no long-term non-macrolide oral antibiotics) in adults with bronchiectasis?

Recommendation

The panel suggests NOT to offer long-term non-macrolide oral antibiotics as a first line treatment to adult patients with bronchiectasis and a high risk of exacerbations (conditional recommendation against the intervention, very low certainty of evidence).

Remarks

 Long-term non-macrolide oral antibiotics may have a role in specific situations where

patients are at high risk of frequent exacerbations and other options such as longterm macrolides are contraindicated or have proven ineffective.

Summary of evidence

Two trials were included, investigating the use of amoxicillin, penicillin and oxytetracycline in patients with bronchiectasis.114,115 Meta-analysis was not possible and so the results of the individual studies are reported narratively. After adjusting for exacerbations frequency in the year before the study, no statistically significant difference in exacerbation rates was observed between the amoxicillin and placebo groups.114 Furthermore, no clinically meaningful reduction in mortality was reported115. Some reductions in breathlessness and sputum volume were noted, although these effects were limited. Currie et al. showed a 58% reduction in sputum volume after 32 weeks in the amoxicillin group compared to 19% in the placebo group.114 Scadding and colleagues found a 26% reduction in sputum volume in the penicillin group, 36% reduction in the oxytetracycline group and 24% reduction in the placebo group after one year. Finally, a slight increase in adverse events and the emergence of potentially pathogenic organisms, as well as a modest rise in antibiotic resistance, were observed in the treatment arms. However, meta-analyses were not feasible due to limited and inconsistently reported data. The trials are also hampered by small population size, questionable inclusion criteria, and, sometimes, a low number of outcome events, resulting in very low certainty of evidence.

Justification of recommendation

The overall risk-benefit balance of long-term non-macrolide oral antibiotics appears to be unfavorable, given the lack of a clear reduction in exacerbations and other clinically relevant outcomes. The available studies are, however, hampered by small populations, unclear reporting of data, questionable inclusion criteria and sometimes a low number of events, resulting in very low certainty of evidence. Therefore, routine use of non-macrolide oral antibiotics is not recommended, as there is limited evidence, a risk of adverse effects and more effective first-line alternatives exist.

There are exceptional circumstances where non-macrolide maintenance antibiotics may be an appropriate treatment for patients with bronchiectasis. This includes in patients at high

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risk of NTM or regions with high NTM prevalence16, or in patients unable to take macrolides due to adverse effects. Therefore, in cases where macrolides are contraindicated or ineffective, and there is clear evidence of infection in respiratory cultures, a trial of long-term, targeted non-macrolide antibiotic therapy may be justified.

Implementation considerations

Physicians and healthcare workers should be advised on the current lack of evidence supporting the use of non-macrolide, long-term antibiotics in bronchiectasis. These treatments should only be considered in patients unable to receive macrolides, with the understanding by healthcare professionals that current data only show limited reduction in shortness of breath and sputum volume.

Monitoring/evaluation

As with any long-term treatment, a formal evaluation of efficacy is recommended and therapy should be discontinued if ineffective.

Future research

RCTs on long-term, non-macrolide oral antibiotics are needed to establish if they reduce exacerbations and improve symptoms, and which patient populations are most likely to benefit.

Figure 3 shows an algorithm for long-term antibiotic use in patients with bronchiectasis. The algorithm first emphasizes antimicrobial stewardship, and that alternative treatments and optimization of management should occur before long-term treatments are considered. Identification of patients at high risk of exacerbations include those with f requent prior exacerbations, severe symptoms, as well as severe exacerbations, while also considering additional risk factors for poor outcomes. In view of the greater evidence for inhaled antibiotics in patients with P. aeruginosa we recommend a different approach for patients with and without P. aeruginosa infection. Patients with P. aeruginosa may receive either a long-term macrolide or long-term inhaled antibiotic as first line treatment, with the choice based on patient preference and an individualized assessment of risks. For patients without P. aeruginosa infection macrolides are a clear first line option. (figure 3).

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 Figure 3. ERS algorithm for long-term antibiotic treatment in patients with bronchiectasis. The identification of high risk individuals is addressed in narrative question 1. Recommendations on long term inhaled antibiotics and macrolides are addressed in the respective PICO questions. Long term oral antibiotics are also addressed in the relevant PICO question. Note that while 12 month reevaluation is suggested as justified in the text, earlier reassessment is needed, particularly in the case of adverse events or clinical deterioration.

PICO QUESTION 6- Eradication

Should eradication treatment be used for patients with isolation of a new pathogenic microorganism(compared to no eradication treatment)?

Recommendation

We suggest to offer eradication treatment to patients with a new isolation of Pseudomonas aeruginosa(conditional recommendation for the intervention, very low certainty of evidence)

Remarks

 A new isolation of P.aeruginosa may refer to the first time a patient has P. aeruginosa

isolated or a further isolation following a prolonged period during which P. aeruginosa

was not detected.

 Eradication practices vary both among panel members and globally. Some clinicians

prescribe systemic antibiotics (e.g 2-week course) followed by a repeat sputum

culture, discontinuing antibiotics if the sample is negative. Others would add inhaled

antibiotics for 4 weeks to 3 months, without rechecking sputum cultures. The 2017

ERS guidelines provide examples of different antibiotic strategies.

Summary of the evidence

No randomized trials comparing eradication with no eradication treatment were identified. The only available evidence comes from before-and-after, observational studies assessing eradication success and clinical outcomes before and after the intervention. All studies examined P. aeruginosa eradication treatment. Six studies were identified, 5 observational studies and 1 randomized trial which evaluated two different eradication regimens . The randomized trial was treated as a before and after observational study for the purposes of analysis.116–121 Pooled data from these studies indicate that eradication was achieved in approximately 40% of patients at 12 months.122 Three studies reported a reduction in exacerbations and/or hospitalisations during the year following the eradication intervention.116,120,121 The certainty of evidence is considered very low, due to the observational nature of the studies, the lack of a control group, and other limitations.

Justification of the recommendation

Despite limited available data, there is overwhelming evidence that chronic infection with P. aeruginosa is associated with increased mortality, exacerbations, hospitalisations and worse quality of life.53,99,123,124 Preventing chronic P. aeruginosa infection is, therefore, of high benefit to patients, and this was confirmed by our panel members with lived experience. The conditional recommendation reflects both the very low certainty of evidence and the concern that while 40% achieve eradication with the current treatments, it is unknown how many patients would achieve spontaneous clearance due to the lack of control groups across studies. The eradication treatment carries burden, particularly if inhaled antibiotics are used, and antibiotic use is associated with a risk of antimicrobial resistance and side effects.

No evidence was identified for the eradication of organisms other than P. aeruginosa and implicit in the above recommendation is that eradication is not recommended routinely for pathogens other than P. aeruginosa

Implementation considerations

The 2017 ERS guidelines provides examples of antibiotic regimens for eradication which typically consist of 2 weeks of oral or IV antibiotics followed by 6 weeks to 3 months of inhaled antibiotics. Practice varies in terms of the antibiotics used, and whether some clinicians will check sputum cultures after the systemic antibiotic phase and discontinue treatment if sputum is negative, while some clinicians will use inhaled antibiotics regardless of whether initial culture conversion is achieved after systemic antibiotics.

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Monitoring and evaluation

Patients undergoing eradication treatment should have sputum cultures performed after the completion of therapy and at 1 year to confirm whether eradication was successful. Patients in whom eradication is not achieved should be managed as having chronic P. aeruginosa infection.

Research priorities

An RCT comparing P. aeruginosa eradication therapy versus symptomatic treatment only is needed to establish the long-term efficacy and safety of this practice. Studies utilising molecular techniques to detect P. aeruginosa should be performed to identify if the organism is truly eradicated or merely suppressed following treatment.

PICO QUESTION 7– Inhaled corticosteroids

Should long-term inhaled corticosteroids be used (compared to no long-term inhaled corticosteroids) in adults with bronchiectasis?

Recommendation

We suggest not to offer long term inhaled corticosteroids to patients with bronchiectasis who do not have coexisting COPD or asthma (conditional recommendation against the intervention, low certainty of evidence)

Remarks

 Patients with bronchiectasisshould be evaluated for the presence of co-existing

asthma and COPD. The presence of bronchiectasis does not alter the

recommendation to use inhaled corticosteroids (ICS) in patients with asthma or in a

subset of patients with COPD. Suspected asthma or COPD should be appropriately

investigated in patients with bronchiectasis.

 There is limited evidence suggesting that ICS may be beneficial in a subgroup of

patients with bronchiectasiswith elevated blood eosinophil counts who do not have

asthma or other eosinophilic conditions. However, no recommendation on ICS use

based on blood eosinophils is currently possible, and we recommend further

research in this group.

 The use of ICS should be reevaluated in patients without a clear indication.

Discontinuation of ICS may be appropriate in some patients.

Summary of evidence

Six randomised trials were identified, one cross-over study of beclomethasone diproprionate 1500 µg per daily125 , RCTs of 400 µg budesonide twice daily, fluticasone 500 µg twice daily126,127, beclomethasone-formoterol 200/12 μg twice daily128, and a randomised trial of 250 µg or 500 µg fluticasone propionate129. Three studies reported no overall differences in

average number of exacerbations or number of participants with an exacerbation in the

groups receiving ICS compared to those receiving no treatment or placebo (MD -0.2, 95% CI -0.57 – 0.16; OR 0.89, 95% CI 0.24 – 3.26, respectively).126,129,130 There were no significant differences in 24-hour sputum volume across three trials (MD -3.37, 95% CI -8.18 – 1.43)125–

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127,129, or in FEV1 in four trials (MD 0.03, 95% CI -0.19 – 0.12).125,127,129,130 There were no significant effects identified for health-related quality of life: in two trials there were no differences in SGRQ total score (MD -3.54, 95% CI -8 – 0.92)129,130 and in one study there was no change in QoL-B score (MD 3.7, 95% CI -9.59 – 16.99).128 There was a significant increase AEs in four studies (OR 3.19, 95% CI 1.34 – 7.61) in those receiving ICS compared to the respective control groups. There was no significant impact on the incidence of hospitalisation in one study (OR 0.20, 95% CI 0.02 – 1.90) and no effect on mortality. No studies reported on occurrence of pneumonia or new NTM isolation.

Certainty of evidence was low as most critical outcomes including exacerbations, quality of life and AEs, were rated as low due to downgrading for factors including imprecision and biases such as lack of blinding and premature trial termination.

Justification of the recommendation

The panel considered there is a lack of evidence of benefit of ICS and a risk of harms associated with this treatment. AEs of ICS are well known and include an increased risk of pneumonia and NTM infection as well as a small but significant increase in systemic adverse effects of corticosteroids.131 20-30% of people with bronchiectasis have comorbid asthma or COPD.35,132 Treatment with ICS is recommended for most individuals with asthma and for a subset of people with COPD who have elevated blood eosinophils and frequent exacerbations.133,134 There is no clear evidence that bronchiectasis should influence the decision to prescribe ICS in these groups.135

Blood eosinophils require further investigation in bronchiectasis as a predictor of ICS efficacy. Around 20% of patients with bronchiectasis have blood eosinophil counts >300cells/µl in the absence of asthma or other eosinophilic conditions.136 There are reports suggesting that in a subset of individuals with elevated blood eosinophils, ICS may be beneficial in improving quality of life and reducing exacerbations but these data are from post hoc analyses and observational studies only and prospective trials are needed.137

Practical considerations

The use of ICS, with or without long-acting beta2 agonists (LABA), is widespread in patients with respiratory symptoms, and misdiagnosis of bronchiectasis as asthma or COPD is not uncommon.35,132,138,139 Many newly diagnosed patients with bronchiectasis are already receiving ICS, and the decision to continue or withdraw ICS when bronchiectasis is diagnosed requires consideration.140 Factors supporting ICS withdrawal include absence of asthma or COPD, supported by established criteria, and low blood eosinophils.141 Conversely, every effort should be made to correctly identify asthma in patients with bronchiectasis as ICS have demonstrated benefit in this group.132 Misdiagnosis of COPD is also common in bronchiectasis, and the ROSE criteria, which define COPD-Bronchiectasis associated in the presence of Radiological bronchiectasis, FEV1/FVC<0.7 (Obstruction), appropriate Symptoms and appropriate Exposures (typically smoking) may support in appropriate diagnostic labelling. 141

Monitoring and evaluation

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If ICS are used, treatment effectiveness should be formally evaluated after a defined period of time, and ICS discontinued if ineffective or if AEs outweigh potential benefits.

Research priorities

A RCT of ICS in bronchiectasis is needed to establish if they can reduce exacerbation frequency and whether blood eosinophil counts predict treatment response. Since ICS is widely used in bronchiectasis, it may be possible to perform a randomized controlled trial of withdrawal of ICS. Further studies are required to understand the role of T2 inflammation in bronchiectasis (not exclusively limited to blood eosinophils) and whether T2 biomarkers can guide treatment.

PICO QUESTION 8 - Pulmonary rehabilitation

Should pulmonary rehabilitation be used (compared to no pulmonary rehabilitation) in adults with bronchiectasis?

Recommendation

We recommend that patients with breathlessness and/or impaired exercise capacity should be offered pulmonary rehabilitation (strong recommendation for the intervention, very low certainty of evidence)

Remarks

 The educational component of pulmonary rehabilitation (PR) should ideally be bronchiectasis specific and include discussion of airway clearance strategies.

 Patients with bronchiectasis should be encouraged to undertake regular physical activity, given its multiple health benefits.

Summary of evidence

We included 7 studies. Compared with usual care, the group of patients with bronchiectasis undergoing PR showed a significant improvement in exercise capacity after the intervention measured by distance (m) covered during 6 minute walking test (6MWT) in three studies (MD 41.13, 95% CI 28.74 – 53.53)142–144, and measured by incremental shuttle walk test (ISWT) in four studies (MD 72.83, 95% CI 51.44 – 94.23).144–147 These differences exceed the minimum clinically important difference. At follow-up, one study showed no difference in 6MWT distance (MD -6.74, 95% CI -29.61 – 16.13)144 and two trials found no difference in ISWT distance (MD 39.41, 95% CI -33.02 – 111.83).144,147 After the intervention, in two studies participants undergoing PR achieved significantly higher number of steps per day than those in the usual care groups (MD 1443, 95% CI 176 - 2709)143,145, although in one study there was no difference in steps at the end of follow up (MD 18.1, 95% CI -2284.05 –

2320.25).145 In two studies, breathlessness measured using the mMRC scale was significantly reduced after the intervention (MD -0.85, 95% CI -1.42 – -0.28).142,143 Healthrelated quality of life measured by the SGRQ total score was significantly improved with PR; in two studies on average SGRQ score was 9.21 points lower (95% CI -13.2 – -5.22) after the intervention142,147, and in one study 8.6 points lower (95% CI -14.34 – -2.86) in the

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rehabilitation group compared with the usual care group at the end of follow up.147 There was no differences in quality of life measured by LCQ in two studies after the intervention (MD

1.2, 95% CI -0.95 – 3.35) or at the end of follow-up (MD 0.98, 95% CI -0.32 – 2.29)144,147, and no difference in QoL-B respiratory domain score in one study after the intervention (MD

3.6, 95% CI -3.18 – 10.38).145 In one study, there was a significant 74% reduction in the odds of a participant experiencing at least one exacerbation during follow-up in the PR group compared to the usual care group (OR 0.26, 95% CI 0.08 – 0.81).144 No significant impact on mortality was observed. No studies reported on occurrence of severe exacerbations.

Overall, there is a substantial benefit of PR in the short-term but most benefits are not sustained during follow-up distant from the intervention..

The certainty of evidence was rated very low due to downgrading based on risk of bias, inconsistency, and imprecision for many key outcomes.

Justification of recommendation

The recommendation is justified by consistent evidence of improvements in quality of life and exercise capacity. Despite the very low certainty of evidence, the strong recommendation is supported by the unequivocal improvement in functional capacity, and consistent results despite small sample sizes. Implementing PR requires substantial investment in resources and trained health professionals, which significantly increases the overall program costs.

Implementation considerations

Effective implementation of PR requires a multifaceted approach to tackle the many implementation pitfalls such as geographic inaccessibility, infrastructure, funding and standardization.148,149 Many rehabilitation programs are designed primary for COPD, and the educational component may not be optimized for patients with bronchiectasis. As bronchiectasis becomes increasingly recognized, the feasibility of tailoring programs to patients with bronchiectasis is expected to improve. Previous guidelines address the delivery of PR.150–152

Monitoring/evaluation

In order to monitor rehabilitation quality and patient evolution, an official ATS/ERS policy statement advises that clinical outcomes must be measured for individual patients and include a standardized assessment of a patients‘ functional exercise capacity, dyspnea, and health status.150,151 Additionally, evaluations of other outcomes are suggested, such as the impact PR has on psychological comorbidity and measurement of the patients‘ experience.

Future research

Future studies should explore how to individualize PR across different settings (home-based, outpatient clinics, hospital-based, community-based and tele-rehabilitation) as well as to evaluate digital tools that could replace face-to-face rehabilitation. Research should also try

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to assess the impact of initiating PR during or immediately after an exacerbation. Finally, pragmatic strategies to sustain benefits of PR should also be a research priority.

Narrative question 2

What diagnostic tests and interventions are currently recommended/used for managing exacerbations?

We suggest the following diagnostic tests be performed during exacerbations (conditional recommendation for the intervention, very low certainty of evidence based on a narrative review of evidence):

Recommendations in current guidelines regarding diagnosis and treatment of exacerbations endorsed by the panel:

 An exacerbation is defined as a worsening of symptoms that exceeds day-to-day

variability and requires a change in management. Core symptoms of exacerbation

include a change in cough, sputum volume and/or consistency, sputum purulence,

dyspnea and/or exercise intolerance, fatigue or malaise and haemoptysis.153 Addition

clinical features are fever, wheezing, general discomfort, anorexia, weight loss,

pleuritic chest pain and changes on chest examination.18,154,155

 Features of a severe exacerbation (defined as requiring hospitalization or

intravenous antibiotic treatment) may include tachypnoea, acute or acute on chronic

respiratory failure, a significant decline in oxygen saturation or respiratory function,

hypercapnia, hemoptysis, new onset of cyanosis, new signs of cor pulmonale,

hemodynamic instability, and/or impaired cognitive function.18,154,156

 At the onset of an exacerbation, a sputum sample for microbiology should ideally be

obtained before initiating antibiotic treatment.18,154,156

 Sputum culture should be repeated, where possible, if there is no response to the

initial antibiotic treatment.154,156,157

We suggest the following interventions to be performed during exacerbations (conditional recommendation for the intervention, very low certainty of evidence based on a narrative review of evidence):

Recommendations in current guidelines regarding interventions endorsed by the panel:

 Antibiotics should be prescribed for an exacerbation, guided by previous microbiology results, local susceptibility patterns, and clinical severity.18,154,156,157

 An adult bronchiectasis self-management plan should include guidance on recognising exacerbations. Providing selected patients the ability to self-administer antibiotics at home with appropriate instruction and education, may allow more prompt treatment.18,154,156,157

 Patients not responding promptly to oral antibiotics or showing signs of a severe exacerbation, should be reviewed to determine if there is a need for a change in treatment, intravenous antibiotic treatment and/or hospitalization.154

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 Airway clearance regimens may need to be adapted in frequency, intensity, and

technique during an exacerbation.65,154

 In general, a 14-day antibiotic course is considered standard, especially in severe

exacerbations or in patients with P. aeruginosa infection. Shorter courses may be

appropriate in patients with mild bronchiectasis, those with infection due to

pathogens more sensitive to antibiotics (e.g. S. pneumoniae), or patients with a rapid

return to baseline symptoms during treatment.18,154,156

Summary of evidence

Exacerbations are a major cause of morbidity, diminished quality of life, and increased mortality in bronchiectasis, making their prevention and management a clinical priority.153 The inherent complexity in defining an exacerbation complicates its diagnosis and management. Moreover, the evidence supporting diagnostic approaches and interventions in current guidelines is largely based on expert opinion and established clinical practice rather than high-quality trials, resulting in an overall low certainty of evidence.18,153,157–159 Evidence suggests that In most exacerbations, there is no change in airway pathogens from stable state and antibiotic treatment is aimed to reduce symptoms, presumably by reducing the bacterial load rather than an attempt to eradicate the chronic infection.83,160 Viruses are a common cause of bronchiectasis exacerbation.83,161 Routinely screening for viruses in bronchiectasis has not been recommended by any guideline to date. Testing, particularly in inpatients presenting with acute respiratory tract infections is common and may influence management if SARS-CoV-2 or influenza are detected.162,163 Table S1 lists documents that contributed to the review of the evidence.

Justification of recommendation

Despite the very low certainty of evidence, the recommendations are justified as many of the suggested practices are already routinely implemented in clinics and hospitals managing patients with bronchiectasis. While specific antibiotic regimens are not detailed due to variations in local practice and resistance patterns, general principles for management of exacerbations can still be established to guide clinical decision-making.

Implementation considerations

The implementation of these recommendations is expected to be straightforward, as they are generally inexpensive and already widely integrated into clinical practice. Given their broad acceptance and routine use in most settings, additional resource allocation or infrastructural changes are unlikely to be necessary for widespread adoption.

Monitoring/evaluation

Exacerbations are common and important events in the natural history of bronchiectasis. Monitoring and evaluation should prioritise assessing their frequency, severity, and response to interventions. Prevention of exacerbations is a major priority and therefore in addition to the acute management of exacerbations patients should be reviewed to determine if they are at high risk of future exacerbations, and preventative measures implemented to reduce future risk.

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Future research

Future research should be focused on the following topics: i) Assessing the presence, severity, and evolution of bronchiectasis exacerbations; ii) Determining the optimal antibiotic management, especially regarding monotherapy versus dual antibiotics and evaluating the role of inhaled antibiotics during exacerbations; iii) Investigating the role of non-antibiotic treatments and identifying causes of exacerbations other than bacterial infection; iv) Establishing the optimal duration of antibiotic treatment particularly for outpatients v) identification of biomarkers that can allow shortening or individualising of antibiotic treatment duration.

Narrative Question 3

What investigations and treatments are currently recommended in a patient with bronchiectasis who is rapidly deteriorating in terms of symptoms or exacerbations?

We suggest the following investigations and management in a deteriorating patient (conditional recommendation for the intervention, very low certainty of evidence based on a narrative review of evidence):

Recommendations in guideline literature on investigations in the deteriorating patient endorsed by the panel:

 Clinical deterioration including increasing exacerbation frequency and/or severity, worsening of symptoms and/or rapid decline in lung function, should result in a comprehensive re-evaluation of the patients and their treatment.18,154

 Adherence to both airway clearance techniques and/or pharmacological treatment should be evaluated.18,65,154

 Underlying diseases other than bronchiectasis should be reviewed to ensure they are being adequately treated.18,154

 Investigation for specific conditions known to be associated with deterioration (e.g ABPA, NTM infection or infection with a new pathogen) should be considered.5,18,154

 Early diagnosis of bronchiectasis, accurate identification and treatment of its underlying cause, adequate management of chronic airway infection, and interventions to prevent exacerbations and control disease may delay disease progression.2,18,154,156

 Repeat chest CT imaging can help to identify several potential causes of deterioration.154

 Repeat testing for NTM should be performed when there are suggestive clinical or radiologic features of NTM infection, particularly in those who deteriorate despite appropriate antibiotics.6,154

Recommendations in guideline literature on treatments endorsed by the panel:

 Deteriorating patients who are not already under the care of a bronchiectasis specialist should be referred to a respiratory clinic with expertise in bronchiectasis.154

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 Current treatment should be reviewed and optimised using a ―treatable traits‖

approach. This includes, but is not limited, to treatment directed at the underlying

aetiology of the patients bronchiectasis, airway clearance and mucoactive

treatments, vaccination status, long-term (inhaled or oral) antibiotic treatment, P.

aeruginosa eradication treatment, long-term inhaled bronchodilator and corticosteroid

treatment, pulmonary rehabilitation, oxygen therapy and non-invasive ventilatory

support where appropriate.2,18,154,156,157

 Lung resection may be considered in highly selected patients with localised disease

whose symptoms are not controlled by medical treatment optimised by a

bronchiectasis specialist.18

 Early referral for lung transplantation is essential in patients with progressive disease

despite optimal medical management. This may include rapidly declining FEV1 or

FEV1 <30%predicted, and/or PaCO2 >50mmHg.18,154

Summary of evidences

Deterioration in patients with bronchiectasis is a critical concern associated with substantial morbidity and mortality, making its management a high priority. While previous guidelines did not explicitly define or address rapidly deteriorating patients, they provided indirect guidance on managing patients with worsening symptoms.18,98 Given the serious clinical implications, ensuring that these patients receive timely investigation, treatment adjustments, and specialist referrals is a fundamental aspect of care.

Current practice for deteriorating patients remains heterogeneous across healthcare providers, as no globally uniform definition of ―deterioration‖ or ―disease progression‖ exists. Typically, patients experiencing rapid worsening of symptoms are referred to a specialist clinic, where their treatment regimen is reevaluated and critically assessed. Key aspects of current care include baseline testing such as chest imaging, lung function and sputum microbiology, revaluation of aetiology, and adjustment of current treatments and preventive strategies. However, important gaps in current practice include treatment adherence assessment, which should be a routine component of patient evaluation, and a shared definition of ―deterioration‖, which is currently inconsistent and variable among healthcare providers.18,98 Table S1 lists documents that contributed to the review of the evidence.

Justification of recommendations

Rapid deterioration in patients with bronchiectasis represents a critical aspect of the disease spectrum, necessitating timely recognition and appropriate management. While most current guideline literature, with the exception of the British Thoracic Society guidelines, do not provide specific guidance for the deteriorating patient, many existing recommendations are applicable to those experiencing increasing exacerbations or worsening symptoms and we therefore extracted these recommendations. These include guidance on follow-up strategies, treatment optimisation, and prevention measures to mitigate disease progression.18,98,157

The accumulated evidence supports early investigation and proactive treatment of patients who have deterioration. By applying these general principles from existing guidelines, clinicians can ensure that deteriorating patients receive timely and individualised management, potentially reducing morbidity and improving long-term outcomes.

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Implementation considerations

As with all aspects of bronchiectasis care, the approach to the deteriorating patient should be personalised and adapted based on the nature of the deterioration, the presenting signs and symptoms, and patients‘ treatable traits. The approach to deteriorating symptoms and reduced lung function may be different as will specific situations such as, a marked increase in haemoptysis, worsening shortness of breath requiring oxygen or non-invasive ventilation, and recurrent exacerbations due to chronic bacterial infections. Figure 4 shows a general approach to the deteriorating patient (the RAPID approach) which needs to be adapted to each individual patient‘s situation.

Monitoring/evaluation

Monitoring and evaluation should focus on early identification and timely intervention for patients experiencing disease deterioration, as this is a common feature of bronchiectasis. Regular clinical assessment, symptom tracking, and objective investigations should be prioritized to detect worsening conditions and guide appropriate treatment. Key aspects of monitoring include evaluating exacerbation frequency, response to treatment, microbiology, respiratory function decline and increased need for oxygen or ventilatory support.

Future research

Future research should focus on i) Improving diagnostic tools to enable faster identification, severity assessment, and objective follow-up of deteriorating patients with bronchiectasis; ii) Determining the optimal timepoint for hospitalisation referral, as well as referral for surgery or lung transplantation; ii) Establishing strategies for measure end-of-life care and palliative management in patients with advanced bronchiectasis.

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Figure 4. The rapidly deteriorating patient treatment algorithm.2,5,6,18,65,154–157

Other treatments

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At the time of writing, a novel anti-inflammatory treatment targeting neutrophilic inflammation, dipeptidyl peptidase-1 (DPP1) inhibition, has shown reduced exacerbations and reduced lung function decline in a 12-month phase 3 trial164, building on the results of several positive phase 2 trials.165–168 The phase 3 trial enrolled patients with bronchiectasis and a history of 2 or more exacerbations in the previous year. DPP1 inhibition is likely to have a role in future management of patients with bronchiectasis at high risk of exacerbations. As this therapy is not available and has not been approved by regulatory authorities at the time of writing, no recommendation is currently possible but this treatment is planned to be addressed in an update of the ERS bronchiectasis guidelines.

Discussion

Bronchiectasis remains a disease with a high unmet need. The evidence base has progressed significantly since the last ERS guidelines in 2017 facilitated a number of important changes in recommendations.169 New recommendations are issued for the first time on severity of disease, co-morbidities and treatable traits and provide detailed summaries of existing guidance on exacerbation management and the deteriorating patient. Substantial changes are made to other aspects of management. Testing for underlying causes, airway clearance, macrolide antibiotics and inhaled antibiotics were all given a conditional recommendation in 2017 and are given a strong recommendation in the present guideline. This reflects a strengthened evidence base, and should result in changes in clinical practice to more proactively use these interventions. For patients with chronic P. aeruginosa infection, macrolides were a second line treatment after failure of an inhaled antibiotic in the 2017 guidelines but are a first line treatment alongside inhaled antibiotics in the 2025 guidelines as a result of improved evidence for both interventions.100,106 A key change in the 2025 guideline is the introduction of individualised risk assessment of patients, where the previous guideline suggested initiating treatments in patients with 3 or more exacerbations per year. Registry data suggests that preventative treatments are generally underutilised in people with bronchiectasis.12,21,140,170,171 The burden of disease is high, and many patients including those with <3 exacerbations per year are at high risk of exacerbation and deterioration. Although it is essential to avoid indiscriminate use of antibiotics, frequent exacerbations promote disease progression and place patients at risk of antimicrobial resistance due to frequent systemic antibiotic treatments. The present guideline promotes a more proactive, patient centred approach to preventative treatment based on identifying patients with high disease activity, and therefore at high risk of progression, and treating before severe deterioration occurs. Elements contributing to the perception and evaluation of disease activity—by both clinicians and patients—usually include the frequency, severity, and impact on quality of life of daily symptoms and exacerbations, the trajectory of lung function over time, as well as some clinical or radiological features such as sputum purulence and the presence of mucus plugs on imaging. Establishing clear definitions of disease activity and disease control will be helpful in future to guide treatment strategies.

Bronchiectasis is a rapidly developing field and it is hoped there will be effective new therapies in the next few years. At present, the 2025 guidelines emphasise the importance of ―doing the simple things well‖ and focusing on identifying the underlying cause, a irway clearance and appropriate pharmacotherapy. Adherence to these guideline recommendations should be evaluated in future through collecting data on the proportion of patients receiving appropriate testing and treatment66, to achieve the ultimate goal of this

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document which is to promote improved treatment for patients with bronchiectasis worldwide.

Summary

The ERS guidelines for the management of bronchiectasis in adults provides an evidencebased framework for the management of patients with bronchiectasis.

References

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Bronchiectasis in Adults and Its Correlation to Disease Severity. Ann Am Thorac Soc. 2015;12(12):1764-1770. doi:10.1513/AnnalsATS.201507-472OC

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References

References

Abstract

Aliberti S, Amati F, Gramegna A, et al. Comparison of different sets of immunological tests to identify treatable immunodeficiencies in adult bronchiectasis patients. ERJ open Res. 2022;8(1).

References

Dudgeon EK, Crichton M, Chalmers JD. -The missing ingredient‖: the patient perspective of health related quality of life in bronchiectasis: a qualitative study. BMC

Dudgeon EK, Crichton M, Chalmers JD. -The missing ingredient‖: the patient perspective of health related quality of life in bronchiectasis: a qualitative study. BMC

Authors

References

Bilton D, Daviskas E, Anderson SD, et al. Phase 3 randomized study of the efficacy and safety of inhaled dry powder mannitol for the symptomatic treatment of noncystic fibrosis bronchiectasis

Bilton D, Daviskas E, Anderson SD, et al. Phase 3 randomized study of the efficacy and safety of inhaled dry powder mannitol for the symptomatic treatment of noncystic fibrosis bronchiectasis

Abstract

Effectiveness of erdosteine in elderly patients with bronchiectasis and hypersecretion: a 15-day, prospective, parallel, open-label, pilot study.

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56. Chang AB, Bell SC, Torzillo PJ, et al. Chronic suppurative lung disease and bronchiectasis in children and adults in Australia and New Zealand Thoracic Society of Australia and New Zealand guidelines. Med

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Bronchiectasis and NTM Research Registry. Chest. 2017;152(6):1120-1127.

doi:10.1016/j.chest.2017.04.167

171. Visser SK, Bye PTP, Fox GJ, et al. Australian adults with bronchiectasis: The first report from the Australian Bronchiectasis Registry. Respir Med. 2019;155:97-103. doi:10.1016/j.rmed.2019.07.016

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Online supplementary materials

Methods search strategy

The Prisma for Searching (PRISMA-Search) was followed to report the searching methodology for this guideline. The search strategies were developed in collaboration with 2 biomedical information specialists (CVM and TV).

Given that for PICO 1, 2, 3, 4, 7 and 8, the goal was to only include randomized controlled trials (RCTs), it was decided to use one broad joint search string for these PICOs, aimed at retrieving all RCTs for bronchiectasis. For PICO 5 (nonmacrolide oral antibiotics) and 6 (pathogen eradication), and for the narrative questions, other study types apart from RCTs could be included. For that reason, more focused search strings were set up for these questions.

The following bibliographic databases were searched for all search questions: : Pubmed (via NCBI, including MEDLINE - coverage from 1946 to date searched), Embase (Embase.com - 1974 to date searched), Web of Science Core Collection (webofscience.com; SCIEXPANDED – 1955 to date searched, SSCI – 1956 to date searched, AHCI – 1975 to date searched, CPCI-S – 1990 to date searched, CPCI-SSH – 1990 to date searched, BKCI-S – 2005 to date searched, BKCI-SSH – 2005 to date searched, ESCI – 2018 to date searched),

and Scopus (Scopus.com - 1788 to date searched).

For PICO 1, 2, 3, 4, 7 and 8, the bibliographic database CENTRAL (via Cochrane Library - unknown inception date to date searched) and two clinical trial registers, namely Clinicaltrials.gov and the International Clinical Trials Registry Platform (ICTRP, WHO), were searched in addition to the databases listed above.

It was deemed unnecessary to search CENTRAL and the two clinical trial registers again for PICO 5 and 6 and the narrative questions, since all RCTs for bronchiectasis were already retrieved with the broad search for PICO 1, 2, 3, 4, 7 and 8. However, during screening for PICO 1,2,3,4,7 and 8 the other PICO‘s and narrative questions were kept in mind and relevant records were annotated towards them.

1) Database searches

a) PICO 1, 2, 3, 4, 7 and 8

For PICO 1, 2, 3, 4, 7 and 8, a comprehensive database search was performed on the 30 th of November 2023. Details of the search strings for each database can be found in the Supplementary Materials. Briefly, two concepts, namely ‗Bronchiectasis‘ and ‗Randomized Controlled Trials‘, were combined with the Boolean operator AND. Within each concept, index terms (where applicable) were combined with free text words (synonyms, related terms, …) to search in title, abstract and keywords with the Boolean operator OR.

b) PICO 5

For PICO 5, a comprehensive database search was performed on the 11th of December

2023. Details of the search strings for each database can be found in the Supplementary Materials. Briefly, two concepts, namely ‗Bronchiectasis‘ and ‗Long term oral antibiotics‘, were combined with the Boolean operator AND. Within each concept, index terms (where applicable) were combined with free text words (synonyms, related terms, …) to search in title, abstract and keywords with the Boolean operator OR. The following antibiotic classes

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and specific antibiotics were searched: fluoroquinolones (ciprofloxacin, levofloxacin, ofloxacin and moxifloxacin), penicillines (amoxicillin and flowacillin), tetracyclines (doxycycline and minocycline), sulfanilamides, trimethoprim/sulfamethoxazole, pyrimidines (trimethoprim) and cephalosporins (cefuroxime).

c) PICO 6

For PICO 6, a comprehensive database search was performed on the 11th of December

2023. Details of the search strings for each database can be found in the Supplementary Materials. Briefly, two concepts, namely ‗Bronchiectasis‘ and ‗Eradication‘, were combined with the Boolean operator AND. Within each concept, index terms (where applicable) were combined with free text words (synonyms, related terms, …) to search in title, abstract and keywords with the Boolean operator OR.

d) Narrative question 1

For Narrative Question 1, a comprehensive database search was performed on the 24 th of January 2024. For this question we searched from the 1st of January 2014 onwards.Details of the search strings for each database can be found in the Supplementary Materials. Briefly, two concepts, namely ‗Bronchiectasis‘ and ‗Etiology/Severity/comorbidity‘, were combined with the Boolean operator AND. Within each concept, index terms (where applicable) were combined with free text words (synonyms, related terms, …) to search in title, abstract and keywords with the Boolean operator OR.

e) Narrative question 2 and 3

For Narrative questions 2 and 3, a comprehensive database search was performed on the 24th of January 2024. Details of the search strings for each database can be found in the Supplementary Materials. Briefly, three concepts, namely ‗Bronchiectasis‘, ‗Eradication‘ and ‗Guideline‘, were combined with the Boolean operator AND. Within each concept, index terms (where applicable) were combined with free text words (synonyms, related terms, …) to search in title, abstract and keywords with the Boolean operator OR.

2) Screening

The retrieved references from each database search (PICO 1,2,3,4,7 and 8/ PICO 5/ PICO 6/ narrative question 1/ narrative questions 2 and 3) were imported into Endnote 20 (EndNote 20 /2013, Clarivate Analytics, Philadelphia, PA USA) and duplicates were removed according to the deduplication method as described by Jane Falconer. After deduplication, the records were imported into Rayyan for title/abstract screening and subsequent full text screening. For the title/abstract screening, each record was screened by at least two reviewers independently and blinded from each other. Conflicts were solved by a third reviewer that did not contribute to the initial title/abstract screening. The included records from the title/abstract screening were imported into Endnote for a full text retrieval. In case Endnote could not retrieve the full text, CVM and TV searched for the full text manually. All retrieved full texts were collected on OneDrive and access was granted to the reviewers. In addition, the bibliographic data of each record to be assessed for full text screening was imported into Rayyan. As such, the reviewers could easily keep track of inclusion/exclusion and annotate the reason for exclusion. Full text screening was performed in duplicate.

Inclusion and exclusion criteria for each individual PICO and narrative question are shown below

General inclusion criteria applicable to all questions

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Inclusion

 Adult patients (age >=18 years)

 A confirmed diagnosis of bronchiectasis (typically by CT imaging but studies utilizing other methodologies will be included)

 Data is available for at least 1 pre-specified outcome for extraction

Exclusion criteria

 Studies limited to specific subtypes of bronchiectasis where the findings would not be applicable for the general population of patients with bronchiectasis (e.g studies exclusively conducted in specific populations of cystic fibrosis, NTM, ABPA or other individual aetiologies)

 Studies in broad patient populations e.g undifferentiated cough, unless data from patients with bronchiectasis can be identified and extracted

 Editorials

 Review articles (with the exception of systematic review and meta-analysis which can be included)

 Non-peer reviewed data such as abstracts

In general our PICO questions addressed intervention A vs absence of intervention A. Therefore this would generally exclude active comparator interventions (where intervention A is tested against intervention B).

Specific inclusion and exclusion criteria

Narrative 1: Studies were excluded if they contained data on less than 30 patients/participants.

PICO 1: airway clearance: We excluded studies with a treatment duration of less than 3 months. We excluded studies comparing two techniques (as the PICO question addresses airway clearance vs no airway clearance).

PICO 2: Mucoactive drugs: Inclusion criteria: for this question we allowed active comparators where the active comparator is not known to have definitive mucoactive properties (isotonic saline as a comparator for hypertonic saline and low dose mannitol as a comparator for standard dose mannitol). We also allowed studies with <3 months duration and studies on specific subtypes of bronchiectasis only for this question.

PICO 3: Inhaled antibiotics: Inclusion criteria: use of inhaled antibiotics during stable state Exclusion criteria: administration of inhaled antibiotics exclusively during an acute exacerbation.

PICO 4: Macrolides: Inclusion criteria: use of macrolides during stable state Exclusion criteria: administration of macrolides exclusively during an acute exacerbation.

PICO 5: Oral antibiotics: Inclusion criteria: use of oral antibiotics during stable state Exclusion criteria: follow-up of <3 months, administration of oral antibiotics exclusively during an acute exacerbation.

PICO 6: Eradication: Inclusion criteria: Use of a formalized antibiotic regimen with the specific objective to eradicate a pathogenic microorganism. Exclusion criteria: treatment with oral or inhaled antibiotics for long term use without a formal eradication regimen.

PICO 7: Inhaled corticosteroids: Inclusion criteria: use of an inhaled regimen containing an inhaled corticosteroid (with or without other drugs such as bronchodilators) with a

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comparator that allows the efficacy of the inhaled corticosteroid to be evaluated i.e a bronchodilator comparator would be permitted.

PICO 8: Pulmonary rehabilitation: Inclusion criteria: Use of a formal rehabilitation, exercise training or similar intervention which contains an exercise component and incorporates a formal evaluation of efficacy.

Narrative 2 and 3: Inclusion criteria: Guidelines or related documents (consensus statements) issued from scientific societies or organisations and containing recommendations relevant to Narrative 2 or Narrative 3 on exacerbations and the deteriorating patient. Exclusion criteria: Commentaries, review articles, original research articles or other documents which do not include explicit evidence based recommendations.

Methodological references

Rethlefsen ML, Kirtley S, Waffenschmidt S, Ayala AP, Moher D, Page MJ, Koffel JB;PRISMA-S Group. PRISMA-S: an extension to the PRISMA Statement for Reporting Literature Searches in Systematic Reviews. Syst Rev.2021;10(1):39. doi: 10.1186/s13643-020-01542-z

Mourad Ouzzani, Hossam Hammady, Zbys Fedorowicz, and Ahmed Elmagarmid. Rayyan-a web and mobile app for systematic reviews. Systematic Reviews(2016) 5:210, DOI:10.1186/s13643-016-0384-4.

Table S1. Guidelines and consensus statements included in the narrative 2 and 3 literature review

|Name of guideline or statement|Publication year|Reference| |---|---|---| |British Thoracic Society guideline for non-CF bronchiectasis.|2008|Thorax.2010 Jul;65 Suppl 1:i1-58. doi: 10.1136/thx.2010.136119.| |Diagnosis and treatment of bronchiectasis. Spanish Society of Pneumology and Thoracic Surgery|2008|Arch Nov;44(11):629-40. doi: 10.1157/13128330.| |Chronic suppurative lung disease and bronchiectasis in children and adults in Australia and New Zealand Thoracic Society of Australia and New Zealand guidelines|2015|Med J Aust. 2015 Jan 19;202(1):21-3. doi: 10.5694/mja14.00287| |The Saudi Thoracic Society guidelines for diagnosis and management of noncystic fibrosis bronchiectasis.|2017|Ann Thorac Med. 2017 Jul- Sep;12(3):135-161. doi: 10.4103/atm.ATM_171_17| |Pulmonary exacerbation in adults with bronchiectasis: a consensus definition for clinical research|2017|Eur Respir J. 2017 Jun 8;49(6):1700051. doi: 10.1183/13993003.00051-2017. Print 2017 Jun.| |European Respiratory Society guidelines for the|2017|Eur Respir J. 2017 Sep 9;50(3):1700629.|

|management of adult bronchiectasis.||doi: [ 10.1183/13993003.00629-2017. Print 2017 Sep.| |---|---|---| |Spanish Guidelines on Treatment of Bronchiectasis in Adults.|2018|Arch Bronconeum (Engl Ed). 2018 Feb;54(2):88-98. doi: 10.1016/j.arbres.2017.07.016. Epub 2017 Nov 9| |Spanish Guidelines on the Evaluation and Diagnosis of Bronchiectasis in Adults|2018|Arch Bronconeum (Engl Ed). 2018 Feb;54(2):79-87. doi: 10.1016/j.arbres.2017.07.015. Epub 2017 Nov 9.| |British Thoracic Society Guideline for bronchiectasis in adults.|2019|Thorax.2019 Jan;74(Suppl 1):1-69. doi: 10.1136/thoraxjnl-2018-212463.| |British Thoracic Society guideline for the use of long-term macrolides in adults with respiratory disease|2020|Thorax 2020;75:370-404| |Thoracic Society of Australia and New Zealand(TSANZ) position statement on chronic suppurative lung disease and bronchiectasis in children, adolescents and adults in Australia and New Zealand|2023|Respirology. 2023 Apr;28(4):339-349. doi: 10.1111/resp.14479. Epub 2023 Mar 2|

Flow Chart, Narrative Question 1

 Flow Chart- Narrative questions 2 and 3

 Flow Chart PICO questions 1,2,3,4,7,8

 Flow Chart PICO Question 5

 Flow Chart PICO 6

 The following section outlines the search terms used and detailed search strategySearch terms used

PICOs 1,2,3,4,7,8

Pubmed (including Medline) 30112023 => 1 + 2 = 2707 results

1. Bronchiectasis

"Bronchiectasis"[Mesh] OR "bronchiectas*"[tiab] OR "bronchoectasia"[tiab]

2. RCT

("Clinical Trial"[pt] OR "placebo"[tiab] OR "drug therapy"[sh] OR "random*"[tiab] OR "RCT"[tiab] OR "trial"[tiab] OR "phase 1"[tiab] OR "phase 2"[tiab] OR "phase 3"[tiab] OR "phase 4"[tiab] OR "phase I"[tiab] OR "phase II"[tiab] OR "phase III"[tiab] OR "phase IV"[tiab] OR "clinical study"[tiab] OR "controlled study"[tiab] OR "controlled design"[tiab] OR "open label"[tiab] OR "double blind*"[tiab] OR "single blind*"[tiab])

NOT ("Animals"[Mesh] NOT "Humans"[Mesh])

Test:

Pico3: (checked and approved)

PMID:

32097051[uid] OR 30975143[uid] OR 28397992[uid] OR 25246664[uid]

Pico2: (checked and approved)

PMID

34760994[uid] OR 29326318[uid] OR 23556995[uid]

Pico1: (checked and approved)

PMID

24625200[uid] OR 30658914[uid] OR 31405826[uid]

Pico4: (checked and approved)

PMID

31405828[uid] OR 23532241[uid]

Pico7: (checked and approved)

PMID

22684355[uid] OR 15741443[uid]

Pico8: (checked and approved)

PMID

24731015[uid] OR 22947443[uid]

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Embase (Embase.com) 30112023 => 1+2 = 2104 results

3. Bronchiectasis

'bronchiectasis'/exp OR 'bronchiectas*':ti,ab,kw OR 'bronchoectasia':ti,ab,kw

4. RCT

('clinical trial'/exp OR 'placebo':ti,ab,kw OR 'random*':ti,ab,kw OR 'RCT':ti,ab,kw OR 'trial':ti,ab,kw OR 'phase 1':ti,ab,kw OR 'phase 2':ti,ab,kw OR 'phase 3':ti,ab,kw OR 'phase 4':ti,ab,kw OR 'phase I':ti,ab,kw OR 'phase II':ti,ab,kw OR 'phase III':ti,ab,kw OR 'phase IV':ti,ab,kw OR 'clinical study':ti,ab,kw OR 'controlled study':ti,ab,kw OR 'controlled design':ti,ab,kw OR 'open label':ti,ab,kw OR 'double blind*':ti,ab,kw OR 'single blind*':ti,ab,kw)

NOT 'conference abstract':it

Scopus 30112023 => 1 + 2 = 1601 results

1. Bronchiectasis

TITLE-ABS("bronchiectas*"OR "bronchoectasia") OR AUTHKEY("bronchiectas*"OR "bronchoectasia")

2. RCT

TITLE-ABS("placebo" OR "random*" OR "RCT" OR "trial" OR "phase 1" OR "phase 2" OR "phase 3" OR "phase 4" OR "phase I" OR "phase II" OR "phase III" OR "phase IV" OR "clinical study" OR "controlled study" OR "controlled design" OR "open label" OR "double blind*" OR "single blind*") OR AUTHKEY("placebo" OR "random*" OR "RCT" OR "trial" OR "phase 1" OR "phase 2" OR "phase 3" OR "phase 4" OR "phase I" OR "phase II" OR "phase III" OR "phase IV" OR "clinical study" OR "controlled study" OR "controlled design" OR "open label" OR "double blind*" OR "single blind*")

WoS Core Collection 30112023 => 1 + 2 = 1133 results

1. Bronchiectasis

TS=("bronchiectas*"OR "bronchoectasia")

2. RCT

TS=("placebo" OR "random*" OR "RCT" OR "trial" OR "phase 1" OR "phase 2" OR "phase 3" OR "phase 4" OR "phase I" OR "phase II" OR "phase III" OR "phase IV" OR "clinical study" OR "controlled study" OR "controlled design" OR "open label" OR "double blind*" OR "single blind*")

NOT DT=("meeting abstract")

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Clinical Trial Registers

3. Clinicaltrials.gov (using the classic website: https://classic.clinicaltrials.gov/)

Bronchiectasis in field 'Condition or disease' and filter "with results" = 27 results on 30/11/2023

Bronchiectasis in field 'Other terms' and filter "with results" = 43 results on 30/11/2023

4. ICTRP

bronchiectas* with results only = 58 results on 40 trials on 30/11/2023

Cochrane CENTRAL 30112023 => 1 = 1478 results (trials)

1. Bronchiectasis

[mh "Bronchiectasis"] OR (bronchiectas* OR "bronchoectasia"):ti,ab,kw

PICO 5

Pubmed (including Medline) 11122023 => 1 + 2 = 2284 results

2. Bronchiectasis

"Bronchiectasis"[Mesh] OR "bronchiectas*"[tiab] OR "bronchoectasia"[tiab]

3. Long term oral antibiotic treatment (excluding long-term macrolides)

"Anti-Bacterial Agents"[Mesh] OR "anti-bacterial"[tiab] OR "antibacterial"[tiab] OR "Bacteriocid*"[tiab] OR "anti-mycobacterial"[tiab] OR "antimycobacterial"[tiab] OR "antibiotic*"[tiab] OR "Anti-Bacterial Agents"[Pharmacological Action] OR

"Fluoroquinolones"[Mesh] OR fluoroquinolon*[tiab] OR ("Quinolones"[Mesh:NoExp] AND "1987":"2001"[mhda]) OR quinolon*[tiab] OR chinolon*[tiab] OR quinolin*[tiab] OR chinolin*[tiab] OR

"Ciprofloxacin"[Mesh:NoExp] OR "cipro*"[tiab] OR "ciprinol"[tiab] OR "aceoto"[tiab] OR "acire"[tiab] OR "alcon cilox"[tiab] OR "apulmiq"[tiab] OR "araxacina"[tiab] OR "aristin-c"[tiab] OR "auripro"[tiab] OR "bacquinor"[tiab] OR "bactiflox"[tiab] OR "baflox"[tiab] OR "basemar"[tiab] OR "battizer"[tiab] OR "baycip"[tiab] OR "bernoflox"[tiab] OR "bivorilan"[tiab] OR "bosix"[tiab] OR "c-flox"[tiab] OR "c-floxacin"[tiab] OR "catex"[tiab] OR "cetraflux"[tiab] OR "cetraxal"[tiab] OR "chinocid"[tiab] OR "cidroxal"[tiab] OR "cifin"[tiab] OR "ciflan"[tiab] OR "ciflo"[tiab] OR "ciflosin"[tiab] OR "ciflot"[tiab] OR "ciflox"[tiab] OR "cifloxin"[tiab] OR "cifox"[tiab] OR "cifran"[tiab] OR "cilab"[tiab] OR "ciloquin"[tiab] OR "ciloxan"[tiab] OR "ciloxin"[tiab] OR "cimogal"[tiab] OR "cinaflox"[tiab] OR "cipad"[tiab] OR "ciperus"[tiab] OR "cipflox"[tiab] OR "ciphin"[tiab] OR "cipide"[tiab] OR "cipio"[tiab] OR "ciplox"[tiab] OR "ciplus"[tiab] OR "cipocin"[tiab] OR "ciprecu"[tiab] OR "ciriax"[tiab] OR "cirok"[tiab] OR

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"cirokan"[tiab] OR "cirox"[tiab] OR "ciroxin"[tiab] OR "citopcin"[tiab] OR "citrovenot"[tiab] OR "cobay"[tiab] OR "corsacin"[tiab] OR "cosflox"[tiab] OR "cuminol"[tiab] OR "cuspis"[tiab] OR "cycin"[tiab] OR "cyfloxin"[tiab] OR "cypral"[tiab] OR "cyprobay"[tiab] OR "cysfec"[tiab] OR "doriman"[tiab] OR "droll"[tiab] OR "eoxin"[tiab] OR "eprocin"[tiab] OR "estecina"[tiab] OR "felixene"[tiab] OR "fimoflox"[tiab] OR "flociprin"[tiab] OR "flontalexin"[tiab] OR "floroxin"[tiab] OR "floxager"[tiab] OR "floxantina"[tiab] OR "floxbio"[tiab] OR "fonterra"[tiab] OR "generflon"[tiab] OR "gerbat"[tiab] OR "ginorectol"[tiab] OR "giroflox"[tiab] OR "gonning"

[tiab] OR "grifociprox"[tiab] OR "h-next"[tiab] OR "holdestin"[tiab] OR "ibixacin"[tiab] OR "inciflox"[tiab] OR "infectocipro"[tiab] OR "inkamil"[tiab] OR "iprolan"[tiab] OR "isotic"[tiab] OR "jayacin"[tiab] OR "k-sacin"[tiab] OR "kenzoflex"[tiab] OR "kinoves"[tiab] OR "kinox"[tiab] OR "kipocin"[tiab] OR "labentrol"[tiab] OR "ladinin"[tiab] OR "limox"[tiab] OR "linhaliq"[tiab] OR "lipoquin"[tiab] OR "lofucin"[tiab] OR "loxan"[tiab] OR "macar"[tiab] OR "medociprin"[tiab] OR "mitroken"[tiab] OR "nafloxin"[tiab] OR "neofloxin"[tiab] OR "nivoflox"[tiab] OR "novidat"[tiab] OR "novoquin"[tiab] OR "oftacilox"[tiab] OR "opthaflox"[tiab] OR "otanol"[tiab] OR "otiprio"[tiab] OR "otociprin"[tiab] OR "otosec"[tiab] OR "phaproxin"[tiab] OR "pharcina"[tiab] OR "poncoflox"[tiab] OR "probiox"[tiab] OR "prociflor"[tiab] OR "procin"[tiab] OR "proflaxin"[tiab] OR "profloxin"[tiab] OR "proksi 250"[tiab] OR "proksi 500"[tiab] OR "proquin"[tiab] OR "proxacin"[tiab] OR "pulmaquin"[tiab] OR "qilaflox"[tiab] OR "qinosyn"[tiab] OR "quilox"[tiab] OR "quinobiotic"[tiab] OR "quinoflox"[tiab] OR "quinolide"[tiab] OR "quinox"[tiab] OR "quintor"[tiab] OR "qupron"[tiab] OR "rancif"[tiab] OR "ravalton"[tiab] OR "revionorm"[tiab] OR "rigoran"[tiab] OR "rofcin"[tiab] OR "roflazin"[tiab] OR "rosacin eye drop"[tiab] OR "samper"[tiab] OR "sarf"[tiab] OR "sepcen"[tiab] OR "septicide"[tiab] OR "septocipro"[tiab] OR "sifloks"[tiab] OR "siprogut"[tiab] OR "siprox"[tiab] OR "sophixin ofteno"[tiab] OR "spitacin"[tiab] OR "strox"[tiab] OR "suiflox"[tiab] OR "superocin"[tiab] OR "syntoflox"[tiab] OR "topistin"[tiab] OR "truoxin"[tiab] OR "ufexil"[tiab] OR "ullax"[tiab] OR "unex"[tiab] OR "unicexal"[tiab] OR "uniflox

References

"ottoflox"[tiab] OR "oxacid"[tiab] OR "oxatrex"[tiab] OR "pharflox"[tiab] OR "praxin"[tiab] OR "puiritol"[tiab] OR "qinolon"[tiab] OR "qipro"[tiab] OR "quinofree"[tiab] OR "quinolon"[tiab] OR "quotavil"[tiab] OR "rilox"[tiab] OR "romacin"[tiab] OR "sinflo"[tiab] OR "surnox"[tiab] OR "tabrin"[tiab] OR "taravid"[tiab] OR "tariflox"[tiab] OR "taroflox"

[tiab] OR "telbit"[tiab] OR "trafloxal"[tiab] OR "tructum"[tiab] OR "urotarivid"[tiab] OR "viotisone"[tiab] OR "visuab"[tiab] OR "zanocin"[tiab] OR "Moxifloxacin"[Mesh] OR "Moxifloxacin*"[tiab] OR Octegra[tiab] OR Proflox[tiab] OR Avelox[tiab] OR Avalox[tiab] OR Izilox[tiab] OR Actira[tiab] OR "avelon"[tiab] OR "bacterol"[tiab] OR "floxamic"[tiab] OR "floxitrat"[tiab] OR "izilox"[tiab] OR "kanavig"[tiab] OR "lifodrox"[tiab] OR "megaxin"[tiab] OR "melocin"[tiab] OR "moksacin"[tiab] OR "monafox"[tiab] OR "moxeza"[tiab] OR "moxibay"[tiab] OR "moxif"[tiab] OR "moxivig"[tiab] OR "octegra"[tiab] OR "proflox"[tiab] OR "tamvelier"[tiab] OR "vamocin"[tiab] OR "vegamox"[tiab] OR "vigamox"[tiab] OR "vigamoxi"[tiab] OR "xiflodrop"[tiab] OR "zimoxin"[tiab] OR "Penicillins"[Mesh] OR penicillin*[tiab] OR "Amoxicillin"[Mesh] OR "Amoxicillin*"[tiab] OR "Amoxycillin*"[tiab] OR "Hydroxyampicillin"[tiab] OR "Actimoxi"[tiab] OR "Clamoxyl"[tiab] OR "Penamox"[tiab] OR "Polymox"[tiab] OR "Trimox"[tiab] OR "Wymox"[tiab] OR "Amoxil"[tiab] OR "a gram"[tiab] OR "abdimox"[tiab] OR "acilina"[tiab] OR "acimox"[tiab] OR "adbiotin"[tiab] OR "agerpen"[tiab] OR "agram"[tiab] OR "alfamox"[tiab] OR "alfoxil"[tiab] OR "almodan"[tiab] OR "almorsan"[tiab] OR "alphamox"[tiab] OR "amagesen solutab"[tiab] OR "ameclina"[tiab] OR "amitron"[tiab] OR "amo-flamisan"[tiab] OR "amo-flamsian"[tiab] OR "amocillin"[tiab] OR "amoclen"[tiab] OR "amodex"[tiab] OR "amoflux"[tiab] OR "amohexal"[tiab] OR "amoli n"[tiab]

OR "amonex"[tiab] OR "amopen"[tiab] OR "amophar ge"[tiab] OR "amosine"[tiab] OR "amoval"[tiab] OR "amoxa"[tiab] OR "amoxal"[tiab] OR "amoxapen"[tiab] OR "amoxaren"[tiab] OR "amoxcil"[tiab] OR "amoxcillin"[tiab] OR "amoxcin"[tiab] OR "amoxibasan"[tiab] OR "amoxicilina"[tiab] OR "amoxiclin"[tiab] OR "amoxicot"[tiab] OR "amoxidal"[tiab] OR "amoxidin"[tiab] OR "amoxidrops"[tiab] OR "amoxihexal"[tiab] OR "amoxillin"[tiab] OR "amoxina"[tiab] OR "amoxipen"[tiab] OR "amoxipenil"[tiab] OR "amoxisol"[tiab] OR "amoxivan"[tiab] OR "amoxivet"[tiab] OR "amoxy"[tiab] OR "amoxydiolan"[tiab] OR "amoxypen"[tiab] OR "ampliron"[tiab] OR "apo-amoxi"[tiab] OR "ardine"[tiab] OR "aroxin"[tiab] OR "azillin"[tiab] OR "bacihexal"[tiab] OR "bactamox"[tiab] OR "bactox ge"[tiab] OR "beamoxy"

[tiab] OR "betamox"[tiab] OR "bimox"[tiab] OR "bintamox"[tiab] OR "biomox"[tiab] OR "biotamoxal"[tiab] OR "bioxidona"[tiab] OR "bioxyllin"[tiab] OR "bristamox"[tiab] OR "broadmetz"[tiab] OR "cabermox"[tiab] OR "cilamox"[tiab] OR "clamox"[tiab] OR "clearamox"[tiab] OR "clonamox"[tiab] OR "coamoxin"[tiab] OR "damoxicil"[tiab] OR "dispermox"[tiab] OR "doxamil"[tiab] OR "draximox"[tiab] OR "edamox"[tiab] OR "efpinex"[tiab] OR "erphamoxy"[tiab] OR "eupen"[tiab] OR "farconcil"[tiab] OR "fisamox"[tiab] OR "flemoxin"[tiab] OR "

References

"moxatag"[tiab] OR "moxilen"[tiab] OR "moxilin"[tiab] OR "moximar"[tiab] OR "moxitab"[tiab] OR "moxtid"[tiab] OR "moxylin"[tiab] OR "moxypen"[tiab] OR "moxyvit"[tiab] OR "neogram"[tiab] OR "novabritine"[tiab] OR "novamox"[tiab] OR "novamoxin"[tiab] OR "novenzymin"[tiab] OR "novoxil"[tiab] OR "nuvosyl"[tiab] OR "optium"[tiab] OR "oramox"[tiab] OR "ospamox"[tiab] OR "pamocil"[tiab] OR "pamoxicillin"[tiab] OR "pamoxin"[tiab] OR "panvilon"[tiab] OR "pasetocin"[tiab] OR "penbiosyn"[tiab] OR "pentyloxycillin"[tiab] OR "pharmoxyl"[tiab] OR "piramox"[tiab] OR "pondnoxcill"[tiab] OR "rancil"[tiab] OR "ranmoxy"[tiab] OR "ranoxil"[tiab] OR "ranoxyl"[tiab] OR "robamox"[tiab] OR "romoxil"[tiab] OR "ronemox"[tiab] OR "saltermox"[tiab] OR "sawacillin"[tiab] OR "sawamezin"[tiab] OR "servamox"[tiab] OR "shamoxil"[tiab] OR "sia-mox"[tiab] OR "sigamopen"[tiab] OR "sil-amox"[tiab] OR "silamox"[tiab] OR "simoxil"[tiab] OR "sintopen"[tiab] OR "solamocta"[tiab] OR "solpenox"[tiab] OR "sumox"[tiab] OR "superpeni"[tiab] OR "teramoxyl"[tiab] OR "tolodina"[tiab] OR "tormoxin"[tiab] OR "triafamox"[tiab] OR "triamoxil"[tiab] OR "trifamox"[tiab] OR "uro clamoxyl"[tiab] OR "uroclamoxyl"[tiab] OR "utimox"[tiab] OR "vastamox"[tiab] OR "velamox"[tiab] OR "vistrep"[tiab] OR "widecillin"[tiab] OR "winpen"[tiab] OR "xiltrop"[tiab] OR "zamocillin"[tiab] OR "zamox"[tiab] OR "zamoxil"[tiab] OR "zerrsox"[tiab] OR "zimox"[tiab] OR

"Co-amoxiclav"[tiab] OR Coamoxiclav[tiab] OR "Amoxi-Clavulanate"[tiab] OR "Amoxclav"[tiab] OR Synulox[tiab] OR Spektramox[tiab] OR Augmentin[tiab] OR Clavulin[tiab] OR "aclam"[tiab] OR "aktil"[tiab] OR "ambilan"[tiab] OR "amocla"[tiab] OR "amoclan"[tiab] OR "amoclane"[tiab] OR "amoclav"[tiab] OR "amoksiklav"[tiab] OR "amolanic"[tiab] OR "amometin"[tiab] OR "amoxi plus"[tiab] OR "amoxiclav"[tiab] OR "amoxiclav-bid"[tiab] OR "amoxiclav-teva"[tiab] OR "amoxsiklav"[tiab] OR "amoxxlin"[tiab] OR "ancla"[tiab] OR "auclatin duo dry syrup"[tiab] OR "augamox"[tiab] OR "augmaxcil"[tiab] OR "augmentan"[tiab] OR "augmentine"[tiab] OR "augmex"[tiab] OR "augpen"[tiab] OR "augucillin duo"[tiab] OR "augurcin"[tiab] OR "ausclav"[tiab] OR "auspilic"[tiab] OR "bactiv"[tiab] OR "bactoclav"[tiab] OR "bioclavid"[tiab] OR "cavumox"[tiab] OR "ciblor"[tiab] OR "clacillin duo dry syrup"[tiab] OR "clamax"[tiab] OR "clamentin"[tiab] OR "clamobit"[tiab] OR "clamonex"[tiab] OR "clamovid"[tiab] OR "clamoxin"[tiab] OR "clamoxyl duo 400"[tiab] OR "clamoxyl duoforte"[tiab] OR "clarin-duo"[tiab] OR "clavam"[tiab] OR "clavamox"[tiab] OR "clavar"[tiab] OR "clavinex"[tiab] OR "clavodar"[tiab] OR "clavoxil"[tiab] OR "clavoxilin plus"[tiab] OR "clavubactin"[tiab] OR "clavucid"[tiab] OR "clavudale"[tiab] OR "clavulox duo"[tiab] OR "clavumox"[tiab] OR "co amoxyclav"[tiab] OR "coamoxyclav"[tiab] OR "cramon duo"[tiab] OR "croanan duo dry syrup"[tiab] OR "curam"[tiab] OR "danoclav"[tiab] OR "darzitil plus"[tiab] OR "duamentin"[tiab] OR "duomox"[tiab] OR "e-moxclav"[tiab] OR "enhancin"[tiab] OR "eumetinex"[tiab] OR "fleming"[tiab] OR "forcid"[tiab] OR "forcid solutab"[tiab] OR "fugentin"[tiab] OR "fullicilina plus"[tiab] OR "gumentin"[tiab] OR "hibiotic"[tiab] OR "inciclav"[tiab] OR "klamonex"[tiab] OR "kmoxilin"[tiab] OR "lactamox"[tiab] OR "lansiclav"[tiab] OR "moxiclav"[tiab] OR "moxicle"[tiab] OR "moxyclav"[tiab] OR "natravox"[tiab] OR "neoduplamox"[tiab] OR "noprilam"[tiab] OR "nufaclav"[tiab] OR "omep plus"[tiab] OR "palentin"[tiab] OR "quali-mentin"[tiab] OR "ranclav"[tiab] OR "spectramox"[tiab] OR "stacillin"[tiab] OR "strenzen"[tiab] OR "suplentin"[tiab] OR "synermox"[tiab] OR "taromentin"[tiab] OR "taromentin es"[tiab] OR "velamox cl"[tiab] OR "vestaclav"[tiab] OR "viaclav"[tiab] OR "vulamox"[tiab] OR "xiclav"[tiab] OR "zami 8503"[tiab] OR

"Floxacillin"[Mesh] OR floxacillin*[tiab] OR Fluorochloroxacillin[tiab] OR Flucloxacillin[tiab] OR "flopen"[tiab] OR "floxapen"[tiab] OR "flucil"[tiab] OR "heraci llin"[tiab] OR "stafoxil"[tiab] OR "staphylex"[tiab] OR

"Tetracyclines"[Mesh] OR "Tetracyclin*"[tiab] OR

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|"Doxycycline"[Mesh] OR "Doxycyclin**[tiab] OR Vibramycin"[tiab] OR Atridox[tiab] OR| |---| |"Doryxtiab] OR Hydramycin[tiab] OR Orrace[tiab] OR Periostatif[tiab] OR Vibra-Tabs[tiab] OR| |"Vibravenos[tiab] OR "adoxa"[tiab] OR "amermycin"[tiab] OR "opprilpron"[tiab] OR "atrax"[tiab]| |"bassado"[tiab] OR "biocolyn"[tiab] OR "biodoxi"[tiab] OR "bronmycin"[tiab] OR "cloran"[tiab]| |"Bassado"[tiab] OR "biocolyn"[tiab] OR "biodoxi"[tiab] OR "bronmycin"[tiab] OR "cloran"[tiab]| |"OR 'dxicldox"[tiab] OR "dentar"[tiab] OR "deoxycycline"[tiab] OR "deoxycycline"[tiab] OR "deoxymycin| |"dispersa"[tiab] OR "deoxymkoin"[tiab] OR "deoxycycline"[tiab] OR "deoxymycin" [tiab] OR "deoxycycline"[tiab] OR "desoxy| |"dotur"[tiab] OR "doxaciclin"[tiab] OR "doxacycline"[tiab] OR "doxiln"[tiab] OR "doxiln"[tiab] OR| |OR 'doxi-sergo"[tiab] OR "doxiciotin[tiab] OR "doxaxciine"[tiab] OR "doxatet"[tiab]| |"doximed"[tiab] OR "doximycin"[tiab] OR "doxin"[tiab] OR "doxynil"[tiab] OR "doxycyclin" [tiab] OR "doxynil"[tiab] OR "doxycyclin" [tiab] OR "doxynil" [tiab] OR "doxycyclin" [tiab] OR "doxynil" [tiab] OR "doxycyclin" [tiab] OR "doxynil" [tiab] OR "doxycyclin" [tiab] OR "doxypen" [tiab] OR "doxycyt" [tiab] OR "doxytrim"[tiab] OR "dumoxymin" [tiab] OR "duracycline"[tiab] OR "efracea"[tiab] OR "esdoxin"[tiab] OR "editoxina" [tiab] OR "gewacyclin"[tiab] OR "branelin" [tiab] OR "idocycline"[tiab] OR "idycycline"[tiab] OR "idocycline"[tiab] OR "medoxxin"[tiab] OR "doxxnotx" [tiab] OR "medoxxin"[tiab] OR "doxxnotx" [tiab] OR "medoxxin"[tiab] OR "doxxnotx" [tiab] OR "medoxxin"[tiab] OR "medoxxin"[tiab] OR "redoxxin"[tiab] OR "medoxxin"[tiab] OR "redoxxin"[tiab] OR "medoxxin"[tiab] OR "medoxxin"[tiab] OR "medoxxin"[tiab] OR "redoxxin"[tiab] OR "medoxxin"[tiab] OR "redoxxin"[tiab] OR "medoxxin"[tiab] OR "redoxxin"[tiab] OR "medoxxin"[tiab] OR "redoxxin"[tiab] OR "medoxxin"[tiab] OR "redoxxin"[tiab] OR "medoxxin" [tiab] OR "medoxxin"[tiab] OR "redoxxin"[tiab] OR "redoxxin" [tiab] OR "medoxxin" [tiab] OR "medoxxin" [tiab] OR "medoxxin" [tiab] OR "medoxxin" [tiab] OR "medoxxin" [tiab] OR "medoxxin" [tiab] OR "medoxxin" [tiab] OR "medoxxin" [tiab] OR "medoxxin" [tiab] OR "medoxxin" [tiab] OR "medoxxin" [tiab] OR "medoxxin" [tiab] OR "medoxxin" [tiab] OR "medoxxin" [tiab] OR "medoxxin" [tiab] OR "medoxxin" [tiab] OR "medoxxin" [tiab] OR "medoxxin" [tiab] OR "medoxxin" [tiab] OR "medoxxin" [tiab] OR "medoxxin" [tiab] OR "medoxxin" [tiab] OR "medoxxin" [tiab] OR "medoxxin" [tiab] OR "medoxxin" [tiab] OR "medoxxin" [tiab] OR "medoxxin" [tiab] OR "medoxxin" [tiab] OR "medox|

unknown [tiab] OR "catin"[tiab] OR "delprim"[tiab] OR "giprim"[tiab] OR "idotrim"[tiab] OR "infectotrimet"[tiab] OR "methoprim"[tiab] OR "monoprim"[tiab] OR "monotrim"[tiab] OR "motrim"[tiab] OR "primosept"[tiab] OR "primsol"[tiab] OR "solotrim"[tiab] OR "syraprim"[tiab] OR "tiempe"[tiab] OR "tmp-ratiopharm"[tiab] OR "tobyprim"[tiab] OR "trimesan"[tiab] OR "trimethoprin"[tiab] OR "trimetoprim"[tiab] OR "trimfect"[tiab] OR "trimono"[tiab] OR "trimopan"[tiab] OR "trinopan"[tiab] OR "triprim"[tiab] OR "trisul"[tiab] OR "uretrim"[tiab] OR "utisept"[tiab] OR "welcoprim"[tiab] OR "wellcoprim"[tiab] OR "Cephalosporins"[Mesh] OR "Cephalosporin*"[tiab] OR cefalosporin*[tiab] OR "Cefuroxime"[Mesh] OR "Cefuroxim*"[tiab] OR Cephuroxim*[tiab] OR Zinacef[tiab] OR Ketocef[tiab] OR "aksef"[tiab] OR "alporin"[tiab] OR "altacef"[tiab] OR "anaptivan"[tiab] OR "aprok"[tiab] OR "aprokam"[tiab] OR "biocefal"[tiab] OR "cefoxurime"[tiab] OR "cefumax"[tiab] OR "ceplus"[tiab] OR "ceroxime"[tiab] OR "curocef"[tiab] OR "curoxim"[tiab] OR "curoxima"[tiab] OR "curoxime"[tiab] OR "eroxmit"[tiab] OR "froxal"[tiab] OR "fucerox"[tiab] OR "furoxime"[tiab] OR "iceca"[tiab] OR "intracef"[tiab] OR "kefazol"[tiab] OR "kefurim"[tiab] OR "kefurox"[tiab] OR "kesint

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References

4. Bronchiectasis

'bronchiectasis'/exp/dm_di,dm_dr,dm_dt,dm_th OR 'bronchiectas*':ti,ab,kw OR 'bronchoectasia':ti,ab,kw OR 'bronchiectasis'/mj

5. Long term oral antibiotic treatment (excluding long-term macrolides)

'antibiotic agent'/de OR 'anti-bacterial':ti,ab,kw OR 'antibacterial':ti,ab,kw OR 'Bacteriocid*':ti,ab,kw OR 'anti-mycobacterial':ti,ab,kw OR 'antimycobacterial':ti,ab,kw OR 'antibiotic*':ti,ab,kw OR

'quinolone derivative'/exp OR 'quinoline derivative'/exp OR 'quinoline derived antiinfective agent'/exp OR fluoroquinolon*:ti,ab,kw OR quinolon*:ti,ab,kw OR chinolon*:ti,ab,kw OR quinolin*:ti,ab,kw OR chinolin*:ti,ab,kw OR

'ciprofloxacin'/exp OR 'cipro*':ti,ab,kw OR 'ciprinol':ti,ab,kw OR 'aceoto':ti,ab,kw OR 'acire':ti,ab,kw OR 'alcon cilox':ti,ab,kw OR 'apulmiq':ti,ab,kw OR 'araxacina':ti,ab,kw OR 'aristin-c':ti,ab,kw OR 'auripro':ti,ab,kw OR 'bacquinor':ti,ab,kw OR 'bactiflox':ti,ab,kw OR 'baflox':ti,ab,kw OR 'basemar':ti,ab,kw OR 'battizer':ti,ab,kw OR 'baycip':ti,ab,kw OR 'bernoflox':ti,ab,kw OR 'bivorilan':ti,ab,kw OR 'bosix':ti,ab,kw OR 'c-flox':ti,ab,kw OR 'cfloxacin':ti,ab,kw OR 'catex':ti,ab,kw OR 'cetraflux':ti,ab,kw OR 'cetraxal':ti,ab,kw OR 'chinocid':ti,ab,kw OR 'cidroxal':ti,ab,kw OR 'cifin':ti,ab,kw OR 'ciflan':ti,ab,kw OR 'ciflo':ti,ab,kw OR 'ciflosin':ti,ab,kw OR 'ciflot':ti,ab,kw OR 'ciflox':ti,ab,kw OR 'cifloxin':ti,ab,kw OR 'cifox':ti,ab,kw OR 'cifran':ti,ab,kw OR 'cilab':ti,ab,kw OR 'ciloquin':ti,ab,kw OR 'ciloxan':ti,ab,kw OR 'ciloxin':ti,ab,kw OR 'cimogal':ti,ab,kw OR 'cinaflox':ti,ab,kw OR 'cipad':ti,ab,kw OR 'ciperus':ti,ab,kw OR 'cipflox':ti,ab,kw OR 'ciphin':ti,ab,kw OR 'cipide':ti,ab,kw OR 'cipio':ti,ab,kw OR 'ciplox':ti,ab,kw OR 'ciplus':ti,ab,kw OR 'cipocin':ti,ab,kw OR 'ciprecu':ti,ab,kw OR 'ciriax':ti,ab,kw OR 'cirok':ti,ab,kw OR 'cirokan':ti,ab,kw OR 'cirox':ti,ab,kw OR 'ciroxin':ti,ab,kw OR 'citopcin':ti,ab,kw OR 'citrovenot':ti,ab,kw OR 'cobay':ti,ab,kw OR 'corsacin':ti,ab,kw OR 'cosflox':ti,ab,kw OR 'cuminol':ti,ab,kw OR 'cuspis':ti,ab,kw OR 'cycin':ti,ab,kw OR 'cyfloxin':ti,ab,kw OR 'cypral':ti,ab,kw OR 'cyprobay':ti,ab,kw OR 'cysfec':ti,ab,kw OR 'doriman':ti,ab,kw OR 'droll':ti,ab,kw OR 'eoxin':ti,ab,kw OR 'eprocin':ti,ab,kw OR 'estecina':ti,ab,kw OR 'felixene':ti,ab,kw OR 'fimoflox':ti,ab,kw OR 'flociprin':ti,ab,kw OR 'flontalexin':ti,ab,kw OR 'floroxin':ti,ab,kw OR 'floxager':ti,ab,kw OR 'floxantina':ti,ab,kw OR 'floxbio':ti,ab,kw OR 'fonterra':ti,ab,kw OR 'generflon':ti,ab,kw OR 'gerbat':ti,ab,kw OR 'ginorectol':ti,ab,kw OR 'giroflox':ti,ab,kw OR 'gonning':ti,ab,kw OR 'grifociprox':ti,ab,kw OR 'h-next':ti,ab,kw OR 'holdestin':ti,ab,kw OR 'ibixacin':ti,ab,kw OR 'inciflox':ti,ab,kw OR 'infectocipro':ti,ab,kw OR 'inkamil':ti,ab,kw OR 'iprolan':ti,ab,kw OR 'isotic':ti,ab,kw OR 'jayacin':ti,ab,kw OR 'ksacin':ti,ab,kw OR 'kenzoflex':ti,ab,kw OR 'kinoves':ti,ab,kw OR 'kinox':ti,ab,kw OR 'kipocin':ti,ab,kw OR 'labentrol':ti,ab,kw OR 'ladinin':ti,ab,kw OR 'limox':ti,ab,kw OR 'linhaliq':ti,ab,kw OR 'lipoquin':ti,ab,kw OR 'lofucin':ti,ab,kw OR 'loxan':ti,ab,kw OR 'macar':ti,ab,kw OR 'medociprin':ti,ab,kw OR 'mitroken':ti,ab,kw OR 'nafloxin':ti,ab,kw OR 'neofloxin':ti,ab,kw OR 'nivoflox':ti,ab,kw OR 'novidat':ti,ab,kw OR 'novoquin':ti,ab,kw OR 'oftacilox':ti,ab,kw OR 'opthaflox':ti,ab,kw OR 'otanol':ti,ab,kw OR 'otiprio':ti,ab,kw OR 'otociprin':ti,ab,kw OR 'otosec':ti,ab,kw OR 'phaproxin':ti,ab,kw OR 'pharcina':ti,ab,kw OR 'poncoflox':ti,ab,kw OR 'probiox':ti,ab,kw OR 'prociflor':ti,ab,kw OR 'procin':ti,ab,kw OR 'proflaxin':ti,ab,kw OR 'profloxin':ti,ab,kw OR 'proksi 250':ti,ab,kw OR 'proksi 500':ti,ab,kw OR 'proquin':ti,ab,kw OR 'proxacin':ti,ab,kw OR 'pulmaquin':ti,ab,kw OR 'qilaflox':ti,ab,kw OR 'qinosyn':ti,ab,kw OR 'quilox':ti,ab,kw OR 'quinobiotic':ti,ab,kw OR 'quinoflox':ti,ab,kw OR 'quinolide':ti,ab,kw OR 'quinox':ti,ab,kw OR 'quintor':ti,ab,kw OR 'qupron':ti,ab,kw OR 'rancif':ti,ab,kw OR 'ravalton':ti,ab,kw OR 'revionorm':ti,ab,kw OR 'rigoran':ti,ab,kw OR 'rofcin':ti,ab,kw OR 'roflazin':ti,ab,kw OR 'rosacin eye drop':ti,ab,kw OR 'samper':ti,ab,kw OR

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'sarf':ti,ab,kw OR 'sepcen':ti,ab,kw OR 'septicide':ti,ab,kw OR 'septocipro':ti,ab,kw OR 'sifloks':ti,ab,kw OR 'siprogut':ti,ab,kw OR 'siprox':ti,ab,kw OR 'sophixin ofteno':ti,ab,kw OR 'spitacin':ti,ab,kw OR 'strox':ti,ab,kw OR 'suiflox':ti,ab,kw OR 'superocin':ti,ab,kw OR 'syntoflox':ti,ab,kw OR 'topistin':ti,ab,kw OR 'truoxin':ti,ab,kw OR 'ufexil':ti,ab,kw OR 'ullax':ti,ab,kw OR 'unex':ti,ab,kw OR 'unicexal':ti,ab,kw OR 'uniflox':ti,ab,kw OR 'urodixin':ti,ab,kw OR 'uroxin':ti,ab,kw OR 'viprolox':ti,ab,kw OR 'zindolin':ti,ab,kw OR 'zipra':ti,ab,kw OR 'zumaflox':ti,ab,kw OR

'levofloxacin'/exp OR ('(S)-isomer' NEXT/3 'Ofloxacin'):ti,ab,kw OR Quixin:ti,ab,kw OR Levaquin:ti,ab,kw OR 'aeroquin':ti,ab,kw OR 'cravit':ti,ab,kw OR 'elequine':ti,ab,kw OR 'eyflox':ti,ab,kw OR 'floxacin':ti,ab,kw OR 'floxel':ti,ab,kw OR 'iquix':ti,ab,kw OR 'leroxacin':ti,ab,kw OR 'lesacin':ti,ab,kw OR 'levokacin':ti,ab,kw OR 'levox':ti,ab,kw OR 'levoxacin':ti,ab,kw OR 'mosardal':ti,ab,kw OR 'nofaxin':ti,ab,kw OR 'oftaquix':ti,ab,kw OR 'oxalux':ti,ab,kw OR 'prixar':ti,ab,kw OR 'quinsair':ti,ab,kw OR 'reskuin':ti,ab,kw OR 'supraflox':ti,ab,kw OR 'tavanic':ti,ab,kw OR 'unibiotic':ti,ab,kw OR 'venaxan':ti,ab,kw OR 'volequin':ti,ab,kw OR

'ofloxacin'/exp OR 'ofloxacin*':ti,ab,kw OR 'tarivid':ti,ab,kw OR 'akilen':ti,ab,kw OR 'audret':ti,ab,kw OR 'bactocin':ti,ab,kw OR 'bioquil':ti,ab,kw OR 'danoflox':ti,ab,kw OR 'effexin':ti,ab,kw OR 'eukinoft':ti,ab,kw OR 'exocin':ti,ab,kw OR 'exocine':ti,ab,kw OR 'flobacin':ti,ab,kw OR 'flodemex':ti,ab,kw OR 'flotavid':ti,ab,kw OR 'flovid':ti,ab,kw OR 'floxal':ti,ab,kw OR 'floxedol':ti,ab,kw OR 'floxigen':ti,ab,kw OR 'floxil':ti,ab,kw OR 'floxin':ti,ab,kw OR 'floxstat':ti,ab,kw OR 'fugacin':ti,ab,kw OR 'grenis-oflo':ti,ab,kw OR 'gyroflox':ti,ab,kw OR 'inoflox':ti,ab,kw OR 'kinflocin':ti,ab,kw OR 'kinoxacin':ti,ab,kw OR 'liflox':ti,ab,kw OR 'loxinter':ti,ab,kw OR 'marfloxacin':ti,ab,kw OR 'medofloxin':ti,ab,kw OR 'medofloxine':ti,ab,kw OR 'mergexin':ti,ab,kw OR 'monoflocet':ti,ab,kw OR 'monoox':ti,ab,kw OR 'novecin':ti,ab,kw OR 'nufafloqo':ti,ab,kw OR 'o-flox':ti,ab,kw OR 'obide':ti,ab,kw OR 'occidal':ti,ab,kw OR 'ocuflox':ti,ab,kw OR 'ofcin':ti,ab,kw OR 'of lin':ti,ab,kw OR 'oflocee':ti,ab,kw OR 'oflocet':ti,ab,kw OR 'oflocin':ti,ab,kw OR 'oflodal':ti,ab,kw OR 'oflodex':ti,ab,kw OR 'oflodinex':ti,ab,kw OR 'oflodura':ti,ab,kw OR 'oflogen':ti,ab,kw OR 'oflohexal':ti,ab,kw OR 'oflovir':ti,ab,kw OR 'oflox':ti,ab,kw OR 'ofloxa-vision':ti,ab,kw OR 'ofloxacino':ti,ab,kw OR 'ofloxamed':ti,ab,kw OR 'ofloxavis':ti,ab,kw OR 'ofloxin':ti,ab,kw OR 'ofus':ti,ab,kw OR 'onexacin':ti,ab,kw OR 'operan':ti,ab,kw OR 'orocin':ti,ab,kw OR 'otiflox':ti,ab,kw OR 'otonil':ti,ab,kw OR 'ottoflox':ti,ab,kw OR 'oxacid':ti,ab,kw OR 'oxatrex':ti,ab,kw OR 'pharflox':ti,ab,kw OR 'praxin':ti,ab,kw OR 'puiritol':ti,ab,kw OR 'qinolon':ti,ab,kw OR 'qipro':ti,ab,kw OR 'quinofree':ti,ab,kw OR 'quinolon':ti,ab,kw OR 'quotavil':ti,ab,kw OR 'rilox':ti,ab,kw OR 'romacin':ti,ab,kw OR 'sinflo':ti,ab,kw OR 'surnox':ti,ab,kw OR 'tabrin':ti,ab,kw OR 'taravid':ti,ab,kw OR 'tariflox':ti,ab,kw OR 'taroflox':ti,ab,kw OR 'telbit':ti,ab,kw OR 'trafloxal':ti,ab,kw OR 'tructum':ti,ab,kw OR 'urotarivid':ti,ab,kw OR 'viotisone':ti,ab,kw OR 'visuab':ti,ab,kw OR 'zanocin':ti,ab,kw OR

'moxifloxacin'/exp OR 'Moxifloxacin*':ti,ab,kw OR Octegra:ti,ab,kw OR Proflox:ti,ab,kw OR Avelox:ti,ab,kw OR Avalox:ti,ab,kw OR Izilox:ti,ab,kw OR Actira:ti,ab,kw OR 'avelon':ti,ab,kw OR 'bacterol':ti,ab,kw OR 'floxamic':ti,ab,kw OR 'floxitrat':ti,ab,kw OR 'izilox':ti,ab,kw OR 'kanavig':ti,ab,kw OR 'lifodrox':ti,ab,kw OR 'megaxin':ti,ab,kw OR 'melocin':ti,ab,kw OR 'moksacin':ti,ab,kw OR 'monafox':ti,ab,kw OR 'moxeza':ti,ab,kw OR 'moxibay':ti,ab,kw OR 'moxif':ti,ab,kw OR 'moxivig':ti,ab,kw OR 'octegra':ti,ab,kw OR 'proflox':ti,ab,kw OR 'tamvelier':ti,ab,kw OR 'vamocin':ti,ab,kw OR 'vegamox':ti,ab,kw OR 'vigamox':ti,ab,kw OR 'vigamoxi':ti,ab,kw OR 'xiflodrop':ti,ab,kw OR 'zimoxin':ti,ab,kw OR

'penicillin derivative'/exp OR penicillin*:ti,ab,kw OR

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'amoxicillin'/exp OR 'Amoxicillin*':ti,ab,kw OR 'Amoxycillin*':ti,ab,kw OR 'Hydroxyampicillin':ti,ab,kw OR 'Actimoxi':ti,ab,kw OR 'Clamoxyl':ti,ab,kw OR 'Penamox':ti,ab,kw OR 'Polymox':ti,ab,kw OR 'Trimox':ti,ab,kw OR 'Wymox':ti,ab,kw OR 'Amoxil':ti,ab,kw OR 'a gram':ti,ab,kw OR 'abdimox':ti,ab,kw OR 'acilina':ti,ab,kw OR 'acimox':ti,ab,kw OR 'adbiotin':ti,ab,kw OR 'agerpen':ti,ab,kw OR 'agram':ti,ab,kw OR 'alfamox':ti,ab,kw OR 'alfoxil':ti,ab,kw OR 'almodan':ti,ab,kw OR 'almorsan':ti,ab,kw OR 'alphamox':ti,ab,kw OR 'amagesen solutab':ti,ab,kw OR 'ameclina':ti,ab,kw OR 'amitron':ti,ab,kw OR 'amo-flamisan':ti,ab,kw OR 'amo-flamsian':ti,ab,kw OR 'amocillin':ti,ab,kw OR 'amoclen':ti,ab,kw OR 'amodex':ti,ab,kw OR 'amoflux':ti,ab,kw OR 'amohexal':ti,ab,kw OR 'amolin':ti,ab,kw OR 'amonex':ti,ab,kw OR 'amopen':ti,ab,kw OR 'amophar ge':ti,ab,kw OR 'amosine':ti,ab,kw OR 'amoval':ti,ab,kw OR 'amoxa':ti,ab,kw OR 'amoxal':ti,ab,kw OR 'amoxapen':ti,ab,kw OR 'amoxaren':ti,ab,kw OR 'amoxcil':ti,ab,kw OR 'amoxcillin':ti,ab,kw OR 'amoxcin':ti,ab,kw OR 'amoxi-basan':ti,ab,kw OR 'amoxicilina':ti,ab,kw OR 'amoxiclin':ti,ab,kw OR 'amoxicot':ti,ab,kw OR 'amoxidal':ti,ab,kw OR 'amoxidin':ti,ab,kw OR 'amoxidrops':ti,ab,kw OR 'amoxihexal':ti,ab,kw OR 'amoxillin':ti,ab,kw OR 'amoxina':ti,ab,kw OR 'amoxipen':ti,ab,kw OR 'amoxipenil':ti,ab,kw OR 'amoxisol':ti,ab,kw OR 'amoxivan':ti,ab,kw OR 'amoxivet':ti,ab,kw OR 'amoxy':ti,ab,kw OR 'amoxy-diolan':ti,ab,kw OR 'amoxypen':ti,ab,kw OR 'ampliron':ti,ab,kw OR 'apoamoxi':ti,ab,kw OR 'ardine':ti,ab,kw OR 'aroxin':ti,ab,kw OR 'azillin':ti,ab,kw OR 'bacihexal':ti,ab,kw OR 'bactamox':ti,ab,kw OR 'bactox ge':ti,ab,kw OR 'beamoxy':ti,ab,kw OR 'betamox':ti,ab,kw OR 'bimox':ti,ab,kw OR 'bintamox':ti,ab,kw OR 'biomox':ti,ab,kw OR 'biotamoxal':ti,ab,kw OR 'bioxidona':ti,ab,kw OR 'bioxyllin':ti,ab,kw OR 'bristamox':ti,ab,kw OR 'broadmetz':ti,ab,kw OR 'cabermox':ti,ab,kw OR 'cilamox':ti,ab,kw OR 'clamox':ti,ab,kw OR 'clearamox':ti,ab,kw OR 'clonamox':ti,ab,kw OR 'coamoxin':ti,ab,kw OR 'damoxicil':ti,ab,kw OR 'dispermox':ti,ab,kw OR 'doxamil':ti,ab,kw OR 'draximox':ti,ab,kw OR 'edamox':ti,ab,kw OR 'efpinex':ti,ab,kw OR 'erphamoxy':ti,ab,kw OR 'eupen':ti,ab,kw OR 'farconcil':ti,ab,kw OR 'fisamox':ti,ab,kw OR 'flemoxin':ti,ab,kw OR 'flemoxine ge':ti,ab,kw OR 'fluamoxina':ti,ab,kw OR 'foxolin':ti,ab,kw OR 'fullcilina':ti,ab,kw OR 'gexcil':ti,ab,kw OR 'gimalxina':ti,ab,kw OR 'glamox':ti,ab,kw OR 'glassatan':ti,ab,kw OR 'gomcillin':ti,ab,kw OR 'grinsul':ti,ab,kw OR 'grunamox':ti,ab,kw OR 'hamoxillin':ti,ab,kw OR 'hiconcil':ti,ab,kw OR 'hidramox':ti,ab,kw OR 'hipen':ti,ab,kw OR 'hosboral':ti,ab,kw OR 'ibamox':ti,ab,kw OR 'ibiamox':ti,ab,kw OR 'ikamoxil':ti,ab,kw OR 'imacillin':ti,ab,kw OR 'imaxilin':ti,ab,kw OR 'inamox':ti,ab,kw OR 'infectomycin':ti,ab,kw OR 'intermox':ti,ab,kw OR 'isimoxin':ti,ab,kw OR 'izoltil':ti,ab,kw OR 'julphamox':ti,ab,kw OR 'jutamox':ti,ab,kw OR 'kamoxin':ti,ab,kw OR 'ladoxillin':ti,ab,kw OR 'lamoxy':ti,ab,kw OR 'larocilin':ti,ab,kw OR 'larocin':ti,ab,kw OR 'larotid':ti,ab,kw OR 'macromox':ti,ab,kw OR 'magnimox':ti,ab,kw OR 'maxamox':ti,ab,kw OR 'maxcil':ti,ab,kw OR 'medimox':ti,ab,kw OR 'meixil':ti,ab,kw OR 'metifarma':ti,ab,kw OR 'mopen':ti,ab,kw OR 'morgenxil':ti,ab,kw OR 'moxacin':ti,ab,kw OR 'moxaline':ti,ab,kw OR 'moxarin':ti,ab,kw OR 'moxatag':ti,ab,kw OR 'moxilen':ti,ab,kw OR 'moxilin':ti,ab,kw OR 'moximar':ti,ab,kw OR 'moxitab':ti,ab,kw OR 'moxtid':ti,ab,kw OR 'moxylin':ti,ab,kw OR 'moxypen':ti,ab,kw OR 'moxyvit':ti,ab,kw OR 'neogram':ti,ab,kw OR 'novabritine':ti,ab,kw OR 'novamox':ti,ab,kw OR 'novamoxin':ti,ab,kw OR 'novenzymin':ti,ab,kw OR 'novoxil':ti,ab,kw OR 'nuvosyl':ti,ab,kw OR 'optium':ti,ab,kw OR 'oramox':ti,ab,kw OR 'ospamox':ti,ab,kw OR 'pamocil':ti,ab,kw OR 'pamoxicillin':ti,ab,kw OR 'pamoxin':ti,ab,kw OR 'panvilon':ti,ab,kw OR 'pasetocin':ti,ab,kw OR 'penbiosyn':ti,ab,kw OR 'pentyloxycillin':ti,ab,kw OR 'pharmoxyl':ti,ab,kw OR 'piramox':ti,ab,kw OR 'pondnoxcill':ti,ab,kw OR 'rancil':ti,ab,kw OR 'ranmoxy':ti,ab,kw OR 'ranoxil':ti,ab,kw OR 'ranoxyl':ti,ab,kw OR 'robamox':ti,ab,kw OR 'romoxil':ti,ab,kw OR 'ronemox':ti,ab,kw OR 'saltermox':ti,ab,kw OR 'sawacillin':ti,ab,kw OR 'sawamezin':ti,ab,kw OR 'servamox':ti,ab,kw OR 'shamoxil':ti,ab,kw OR 'sia-mox':ti,ab,kw OR 'sigamopen':ti,ab,kw OR 'sil-a-mox':ti,ab,kw OR 'silamox':ti,ab,kw OR 'simoxil':ti,ab,kw OR 'sintopen':ti,ab,kw OR 'solamocta':ti,ab,kw OR 'solpenox':ti,ab,kw OR 'sumox':ti,ab,kw OR

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'superpeni':ti,ab,kw OR 'teramoxyl':ti,ab,kw OR 'tolodina':ti,ab,kw OR 'tormoxin':ti,ab,kw OR 'triafamox':ti,ab,kw OR 'triamoxil':ti,ab,kw OR 'trifamox':ti,ab,kw OR 'uro clamoxyl':ti,ab,kw OR 'uroclamoxyl':ti,ab,kw OR 'utimox':ti,ab,kw OR 'vastamox':ti,ab,kw OR 'velamox':ti,ab,kw OR 'vistrep':ti,ab,kw OR 'widecillin':ti,ab,kw OR 'winpen':ti,ab,kw OR 'xiltrop':ti,ab,kw OR 'zamocillin':ti,ab,kw OR 'zamox':ti,ab,kw OR 'zamoxil':ti,ab,kw OR 'zerrsox':ti,ab,kw OR 'zimox':ti,ab,kw OR

'amoxicillin plus clavulanic acid'/exp OR 'Co-amoxiclav':ti,ab,kw OR Coamoxiclav:ti,ab,kw OR 'Amoxi-Clavulanate':ti,ab,kw OR 'Amox-clav':ti,ab,kw OR Synulox:ti,ab,kw OR Spektramox:ti,ab,kw OR Augmentin:ti,ab,kw OR Clavulin:ti,ab,kw OR 'aclam':ti,ab,kw OR 'aktil':ti,ab,kw OR 'ambilan':ti,ab,kw OR 'amocla':ti,ab,kw OR 'amoclan':ti,ab,kw OR 'amoclane':ti,ab,kw OR 'amoclav':ti,ab,kw OR 'amoksiklav':ti,ab,kw OR 'amolanic':ti,ab,kw OR 'amometin':ti,ab,kw OR 'amoxi plus':ti,ab,kw OR 'amoxiclav':ti,ab,kw OR 'amoxiclav -bid':ti,ab,kw OR 'amoxiclav-teva':ti,ab,kw OR 'amoxsiklav':ti,ab,kw OR 'amoxxlin':ti,ab,kw OR 'ancla':ti,ab,kw OR 'auclatin duo dry syrup':ti,ab,kw OR 'augamox':ti,ab,kw OR 'augmaxcil':ti,ab,kw OR 'augmentan':ti,ab,kw OR 'augmentine':ti,ab,kw OR 'augmex':ti,ab,kw OR 'augpen':ti,ab,kw OR 'augucillin duo':ti,ab,kw OR 'augurcin':ti,ab,kw OR 'ausclav':ti,ab,kw OR 'auspilic':ti,ab,kw OR 'bactiv':ti,ab,kw OR 'bactoclav':ti,ab,kw OR 'bioclavid':ti,ab,kw OR 'cavumox':ti,ab,kw OR 'ciblor':ti,ab,kw OR 'clacillin duo dry syrup':ti,ab,kw OR 'clamax':ti,ab,kw OR 'clamentin':ti,ab,kw OR 'clamobit':ti,ab,kw OR 'clamonex':ti,ab,kw OR 'clamovid':ti,ab,kw OR 'clamoxin':ti,ab,kw OR 'clamoxyl duo 400':ti,ab,kw OR 'clamoxyl duoforte':ti,ab,kw OR 'clarin-duo':ti,ab,kw OR 'clavam':ti,ab,kw OR 'clavamox':ti,ab,kw OR 'clavar':ti,ab,kw OR 'clavinex':ti,ab,kw OR 'clavodar':ti,ab,kw OR 'clavoxil':ti,ab,kw OR 'clavoxilin plus':ti,ab,kw OR 'clavubactin':ti,ab,kw OR 'clavucid':ti,ab,kw OR 'clavudale':ti,ab,kw OR 'clavulox duo':ti,ab,kw OR 'clavumox':ti,ab,kw OR 'co amoxyclav':ti,ab,kw OR 'coamoxyclav':ti,ab,kw OR 'cramon duo':ti,ab,kw OR 'croanan duo dry syrup':ti,ab,kw OR 'curam':ti,ab,kw OR 'danoclav':ti,ab,kw OR 'darzitil plus':ti,ab,kw OR 'duamentin':ti,ab,kw OR 'duomox':ti,ab,kw OR 'e-moxclav':ti,ab,kw OR 'enhancin':ti,ab,kw OR 'eumetinex':ti,ab,kw OR 'fleming':ti,ab,kw OR 'forcid':ti,ab,kw OR 'forcid solutab':ti,ab,kw OR 'fugentin':ti,ab,kw OR 'fullicilina plus':ti,ab,kw OR 'gumentin':ti,ab,kw OR 'hibiotic':ti,ab,kw OR 'inciclav':ti,ab,kw OR 'klamonex':ti,ab,kw OR 'kmoxilin':ti,ab,kw OR 'lactamox':ti,ab,kw OR 'lansiclav':ti,ab,kw OR 'moxiclav':ti,ab,kw OR 'moxicle':ti,ab,kw OR 'moxyclav':ti,ab,kw OR 'natravox':ti,ab,kw OR 'neoduplamox':ti,ab,kw OR 'noprilam':ti,ab,kw OR 'nufaclav':ti,ab,kw OR 'omep plus':ti,ab,kw OR 'palentin':ti,ab,kw OR 'quali-mentin':ti,ab,kw OR 'ranclav':ti,ab,kw OR 'spectramox':ti,ab,kw OR 'stacillin':ti,ab,kw OR 'strenzen':ti,ab,kw OR 'suplentin':ti,ab,kw OR 'synermox':ti,ab,kw OR 'taromentin':ti,ab,kw OR 'taromentin es':ti,ab,kw OR 'velamox cl':ti,ab,kw OR 'vestaclav':ti,ab,kw OR 'viaclav':ti,ab,kw OR 'vulamox':ti,ab,kw OR 'xiclav':ti,ab,kw OR 'zami 8503':ti,ab,kw OR

'flucloxacillin'/exp OR floxacillin*:ti,ab,kw OR Fluorochloroxacillin:ti,ab,kw OR Flucloxacillin:ti,ab,kw OR 'flopen':ti,ab,kw OR 'floxapen':ti,ab,kw OR 'flucil':ti,ab,kw OR 'heracillin':ti,ab,kw OR 'stafoxil':ti,ab,kw OR 'staphylex':ti,ab,kw OR

'tetracycline derivative'/exp OR 'Tetracyclin*':ti,ab,kw OR

'doxycycline'/exp OR 'Doxycyclin*':ti,ab,kw OR Vibramycin*:ti,ab,kw OR Atridox:ti,ab,kw OR Doryx:ti,ab,kw OR Hydramycin:ti,ab,kw OR Oracea:ti,ab,kw OR Periostat:ti,ab,kw OR VibraTabs:ti,ab,kw OR Vibravenos:ti,ab,kw OR 'adoxa':ti,ab,kw OR 'amermycin':ti,ab,kw OR 'apprilon':ti,ab,kw OR 'atrax':ti,ab,kw OR 'azudoxat':ti,ab,kw OR 'bactidox':ti,ab,kw OR 'banndoclin':ti,ab,kw OR 'basedillin':ti,ab,kw OR 'bassado':ti,ab,kw OR 'biocolyn':ti,ab,kw OR 'biodoxi':ti,ab,kw OR 'bronmycin':ti,ab,kw OR 'cloran':ti,ab,kw OR 'cyclidox':ti,ab,kw OR 'dentistar':ti,ab,kw OR 'deoxycycline':ti,ab,kw OR 'deoxymycin dispersal':ti,ab,kw OR

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'deoxymykoin':ti,ab,kw

OR

'deoxyoxytetracycline':ti,ab,kw

OR

'desoxy oxytetracycline':ti,ab,kw OR 'desoxycycline':ti,ab,kw OR 'doinmycin':ti,ab,kw OR 'dosil':ti,ab,kw OR 'dotur':ti,ab,kw OR 'doxaciclin':ti,ab,kw OR 'doxacycline':ti,ab,kw OR 'doxat':ti,ab,kw OR 'doxatet':ti,ab,kw OR 'doxi-sergo':ti,ab,kw OR 'doxibiotic':ti,ab,kw OR 'doxicycline':ti,ab,kw OR 'doxilin':ti,ab,kw OR 'doximed':ti,ab,kw OR 'doximycin':ti,ab,kw OR 'doxin':ti,ab,kw OR 'doxine':ti,ab,kw OR 'doxirobe':ti,ab,kw OR 'doxocycline':ti,ab,kw OR 'doxsig':ti,ab,kw OR 'doxy':ti,ab,kw OR 'doxybiocin':ti,ab,kw OR 'doxycen':ti,ab,kw OR 'doxychel':ti,ab,kw OR 'doxycin':ti,ab,kw OR 'doxylag':ti,ab,kw OR 'doxylin':ti,ab,kw OR 'doxymycin':ti,ab,kw OR 'doxypuren':ti,ab,kw OR 'doxytec':ti,ab,kw OR 'doxytrim':ti,ab,kw OR 'dumoxin':ti,ab,kw OR 'duracycline':ti,ab,kw OR 'efracea':ti,ab,kw OR 'esdoxin':ti,ab,kw OR 'etidoxina':ti,ab,kw OR 'gewacyclin':ti,ab,kw OR 'ibralene':ti,ab,kw OR 'idocyclin':ti,ab,kw OR 'idocyklin':ti,ab,kw OR 'interdoxin':ti,ab,kw OR 'investin':ti,ab,kw OR 'longamycin':ti,ab,kw OR 'lydox':ti,ab,kw OR 'magdrin':ti,ab,kw OR 'medomycin':ti,ab,kw OR 'mespafin':ti,ab,kw OR 'mildox':ti,ab,kw OR 'miraclin':ti,ab,kw OR 'monodox':ti,ab,kw OR 'nanodox':ti,ab,kw OR 'nordox':ti,ab,kw OR 'oraycea':ti,ab,kw OR 'paldomycin':ti,ab,kw OR 'pernox gel':ti,ab,kw OR 'radox':ti,ab,kw OR 'remycin':ti,ab,kw OR 'respidox':ti,ab,kw OR 'roximycin':ti,ab,kw OR 'serodoxy':ti,ab,kw OR 'servidoxine':ti,ab,kw OR 'servidoxyne':ti,ab,kw OR 'siadocin':ti,ab,kw OR 'siclidon':ti,ab,kw OR 'sigadoxin':ti,ab,kw OR 'spanor':ti,ab,kw OR 'supracyclin':ti,ab,kw OR 'supramycina':ti,ab,kw OR 'tenutan':ti,ab,kw OR 'tolexine':ti,ab,kw OR 'torymycin':ti,ab,kw OR 'tsurupioxin':ti,ab,kw OR 'unidox':ti,ab,kw OR 'veemycin':ti,ab,kw OR 'viadoxin':ti,ab,kw OR 'vibra s':ti,ab,kw OR 'vibra-s':ti,ab,kw OR 'vibrabiotic':ti,ab,kw OR 'vibracina':ti,ab,kw OR 'vibradox':ti,ab,kw OR 'vibramicina':ti,ab,kw OR 'vibraveineuse':ti,ab,kw OR 'vibravet':ti,ab,kw OR 'viradoxyl-n':ti,ab,kw OR 'wanmycin':ti,ab,kw OR 'xyrosa':ti,ab,kw OR 'zadorin':ti,ab,kw OR 'zenavod':ti,ab,kw OR

'minocycline'/exp OR 'Minocyclin*':ti,ab,kw OR 'Minox 50':ti,ab,kw OR Aknemin:ti,ab,kw OR 'Aknin-Mino':ti,ab,kw OR Aknosan:ti,ab,kw OR Mynocine:ti,ab,kw OR Arestin:ti,ab,kw OR Blemix:ti,ab,kw OR Cyclomin:ti,ab,kw OR Cyclops:ti,ab,kw OR Dentomycin:ti,ab,kw OR Dynacin:ti,ab,kw OR 'Icht-Oral':ti,ab,kw OR Klinomycin:ti,ab,kw OR Lederderm:ti,ab,kw OR Mestacine:ti,ab,kw OR Minakne:ti,ab,kw OR 'Mino-Wolff':ti,ab,kw OR Minocin:ti,ab,kw OR Minoclir:ti,ab,kw OR Minolis:ti,ab,kw OR Minomycin:ti,ab,kw OR Minoplus:ti,ab,kw OR Minotab:ti,ab,kw OR Akamin:ti,ab,kw OR 'Akne-Puren':ti,ab,kw OR 'amzeeq':ti,ab,kw OR 'borymycin':ti,ab,kw OR 'cipancin':ti,ab,kw OR 'cyclimycin':ti,ab,kw OR 'cynomycin':ti,ab,kw OR 'klinotab':ti,ab,kw OR 'kyno':ti,ab,kw OR 'logryx':ti,ab,kw OR 'menocycline':ti,ab,kw OR 'micromycin':ti,ab,kw OR 'minaxen':ti,ab,kw OR 'mino-50':ti,ab,kw OR 'minoclin':ti,ab,kw OR 'minocyn':ti,ab,kw OR 'minogalen':ti,ab,kw OR 'minoline':ti,ab,kw OR 'minolira':ti,ab,kw OR 'minomax':ti,ab,kw OR 'minosil':ti,ab,kw OR 'minostad':ti,ab,kw OR 'minotrex':ti,ab,kw OR 'minoz ep':ti,ab,kw OR 'mirosin':ti,ab,kw OR 'parocline':ti,ab,kw OR 'periofeel':ti,ab,kw OR 'romin':ti,ab,kw OR 'sebomir':ti,ab,kw OR 'skinocyclin':ti,ab,kw OR 'solodyn':ti,ab,kw OR 'spicline':ti,ab,kw OR 'vectran':ti,ab,kw OR 'vectrin':ti,ab,kw OR 'ximino':ti,ab,kw OR 'zilxi':ti,ab,kw OR

'sulfonamide'/exp OR sulfanilamide*:ti,ab,kw OR sulfonamide*:ti,ab,kw OR sulphanilamide*:ti,ab,kw OR sulphonamide*:ti,ab,kw OR

'cotrimoxazole'/exp OR Centrin:ti,ab,kw OR Cotrimoxazole:ti,ab,kw OR 'CoTrimoxazole':ti,ab,kw OR Eslectin:ti,ab,kw OR Insozalin:ti,ab,kw OR Trimezol*:ti,ab,kw OR Centran:ti,ab,kw OR Trimedin:ti,ab,kw OR Septrin*:ti,ab,kw OR Bactifor:ti,ab,kw OR Sumetrolim:ti,ab,kw OR Abactrim:ti,ab,kw OR Bactrim:ti,ab,kw OR Biseptol:ti,ab,kw OR Biseptol480:ti,ab,kw OR Drylin:ti,ab,kw OR Eusaprim:ti,ab,kw OR Kepinol:ti,ab,kw OR Lescot:ti,ab,kw OR Metomide:ti,ab,kw OR Oriprim:ti,ab,kw OR Septra:ti,ab,kw OR Sulprim:ti,ab,kw OR Trimosulfa:ti,ab,kw OR 'abactrin':ti,ab,kw OR 'alfatrim':ti,ab,kw OR 'apo

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sulfatrim':ti,ab,kw OR 'bactar':ti,ab,kw OR 'bactipront':ti,ab,kw OR 'bactoreduct forte':ti,ab,kw OR 'bactramin':ti,ab,kw OR 'bactrimel':ti,ab,kw OR 'bethaprim':ti,ab,kw OR 'bispetol':ti,ab,kw OR 'chemotrim':ti,ab,kw OR 'comox':ti,ab,kw OR 'comoxol':ti,ab,kw OR 'cotrim':ti,ab,kw OR 'cotrimoxazol forte':ti,ab,kw OR 'cotrimstada forte':ti,ab,kw OR 'deprim':ti,ab,kw OR 'deprim forte':ti,ab,kw OR 'duobact':ti,ab,kw OR 'duobiocin':ti,ab,kw OR 'duobiocin forte':ti,ab,kw OR 'duratrimet':ti,ab,kw OR 'eltrianyl':ti,ab,kw OR 'escoprim':ti,ab,kw OR 'espectrin':ti,ab,kw OR 'fectrim':ti,ab,kw OR 'groprim':ti,ab,kw OR 'helveprim':ti,ab,kw OR 'imexim':ti,ab,kw OR 'infectrim':ti,ab,kw OR 'lagaprim':ti,ab,kw OR 'lagatrim':ti,ab,kw OR 'linaris':ti,ab,kw OR 'microtrim':ti,ab,kw OR 'neoprim':ti,ab,kw OR 'nopil':ti,ab,kw OR 'oecotrim':ti,ab,kw OR 'omsat':ti,ab,kw OR 'oribact':ti,ab,kw OR 'pharmaprim':ti,ab,kw OR 'potesept':ti,ab,kw OR 'resprim':ti,ab,kw OR 'resprin':ti,ab,kw OR 'scanprin':ti,ab,kw OR 'septran':ti,ab,kw OR 'septrim':ti,ab,kw OR 'sigaprim':ti,ab,kw OR 'sinersol':ti,ab,kw OR 'soltrim':ti,ab,kw OR 'sulfamethoprim':ti,ab,kw OR 'sulfaprim':ti,ab,kw OR 'sulfatrim':ti,ab,kw OR 'sulfotrim':ti,ab,kw OR 'sulmeprim':ti,ab,kw OR 'sumetrolin':ti,ab,kw OR 'supracombin':ti,ab,kw OR 'thiocuran':ti,ab,kw OR 'tms forte':ti,ab,kw OR 'trib':ti,ab,kw OR 'trigonyl':ti,ab,kw OR 'trimeth/sulfa':ti,ab,kw

OR

'trimetoprim-sulfa':ti,ab,kw

OR 'trimetoprimsulfamethoxazole':ti,ab,kw OR 'trimforte':ti,ab,kw OR 'trimoxazole':ti,ab,kw OR 'trimoxol':ti,ab,kw OR 'uro ts d':ti,ab,kw OR 'uroplus ds':ti,ab,kw OR 'uroplus ss':ti,ab,kw OR

'pyrimidine derivative'/exp OR pyrimidin*:ti,ab,kw OR

'trimethoprim'/exp OR trimethoprim*:ti,ab,kw OR trimpex:ti,ab,kw OR proloprim:ti,ab,kw OR 'abaprim':ti,ab,kw OR 'alprim':ti,ab,kw OR 'catin':ti,ab,kw OR 'delprim':ti,ab,kw OR 'giprim':ti,ab,kw OR 'idotrim':ti,ab,kw OR 'infectotrimet':ti,ab,kw OR 'methoprim':ti,ab,kw OR 'monoprim':ti,ab,kw OR 'monotrim':ti,ab,kw OR 'motrim':ti,ab,kw OR 'primosept':ti,ab,kw OR 'primsol':ti,ab,kw OR 'solotrim':ti,ab,kw OR 'syraprim':ti,ab,kw OR 'tiempe':ti,ab,kw OR 'tmpratiopharm':ti,ab,kw OR 'tobyprim':ti,ab,kw OR 'trimesan':ti,ab,kw OR 'trimethoprin':ti,ab,kw OR 'trimetoprim':ti,ab,kw OR 'trimfect':ti,ab,kw OR 'trimono':ti,ab,kw OR 'trimopan':ti,ab,kw OR 'trinopan':ti,ab,kw OR 'triprim':ti,ab,kw OR 'trisul':ti,ab,kw OR 'uretrim':ti,ab,kw OR 'utisept':ti,ab,kw OR 'welcoprim':ti,ab,kw OR 'wellcoprim':ti,ab,kw OR

'cephalosporin derivative'/exp OR 'Cephalosporin*':ti,ab,kw OR cefalosporin*:ti,ab,kw OR

'cefuroxime'/exp OR 'Cefuroxim*':ti,ab,kw OR Cephuroxim*:ti,ab,kw OR Zinacef:ti,ab,kw OR Ketocef:ti,ab,kw OR 'aksef':ti,ab,kw OR 'alporin':ti,ab,kw OR 'altacef':ti,ab,kw OR 'anaptivan':ti,ab,kw OR 'aprok':ti,ab,kw OR 'aprokam':ti,ab,kw OR 'biocefal':ti,ab,kw OR 'cefoxurime':ti,ab,kw OR 'cefumax':ti,ab,kw OR 'ceplus':ti,ab,kw OR 'ceroxime':ti,ab,kw OR 'curocef':ti,ab,kw OR 'curoxim':ti,ab,kw OR 'curoxima':ti,ab,kw OR 'curoxime':ti,ab,kw OR 'eroxmit':ti,ab,kw OR 'froxal':ti,ab,kw OR 'fucerox':ti,ab,kw OR 'furoxime':ti,ab,kw OR 'iceca':ti,ab,kw OR 'intracef':ti,ab,kw OR 'kefazol':ti,ab,kw OR 'kefurim':ti,ab,kw OR 'kefurox':ti,ab,kw OR 'kesint':ti,ab,kw OR 'laxinat':ti,ab,kw OR 'maxil':ti,ab,kw OR 'normafenac':ti,ab,kw OR 'polixima':ti,ab,kw OR 'prokam':ti,ab,kw OR 'supacef':ti,ab,kw OR 'tarsime':ti,ab,kw OR 'ucefaxim':ti,ab,kw OR 'ultroxim':ti,ab,kw OR 'uroxime':ti,ab,kw OR 'vekfazolin':ti,ab,kw OR 'ximaract':ti,ab,kw OR 'zinocef':ti,ab,kw

NOT 'conference abstract':it

Scopus 11122023 => 1 + 2 = 2132 results

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1. Bronchiectasis

TITLE-ABS("bronchiectas*"OR "bronchoectasia") OR AUTHKEY("bronchiectas*"OR "bronchoectasia")

2. Antibiotics

TITLE-ABS("anti-bacterial" OR "antibacterial" OR "Bacteriocid*" OR "anti-mycobacterial" OR "antimycobacterial" OR "antibiotic*" OR

"fluoroquinolon*" OR "quinolon*" OR "chinolon*" OR "quinolin*" OR "chinolin*" OR

"cipro*" OR "ciprinol" OR "aceoto" OR "acire" OR "alcon cilox" OR "apulmiq" OR "araxacina" OR "aristin-c" OR "auripro" OR "bacquinor" OR "bactiflox" OR "baflox" OR "basemar" OR "battizer" OR "baycip" OR "bernoflox" OR "bivorilan" OR "bosix" OR "c-flox" OR "c-floxacin" OR "catex" OR "cetraflux" OR "cetraxal" OR "chinocid" OR "cidroxal" OR "cifin" OR "ciflan" OR "ciflo" OR "ciflosin" OR "ciflot" OR "ciflox" OR "cifloxin" OR "cifox" OR "cifran" OR "cilab" OR "ciloquin" OR "ciloxan" OR "ciloxin" OR "cimogal" OR "cinaflox" OR "cipad" OR "ciperus" OR "cipflox" OR "ciphin" OR "cipide" OR "cipio" OR "ciplox" OR "ciplus" OR "cipocin" OR "ciprecu" OR "ciriax" OR "cirok" OR "cirokan" OR "cirox" OR "ciroxin" OR "citopcin" OR "citrovenot" OR "cobay" OR "corsacin" OR "cosflox" OR "cuminol" OR "cuspis" OR "cycin" OR "cyfloxin" OR "cypral" OR "cyprobay" OR "cysfec" OR "doriman" OR "droll" OR "eoxin" OR "eprocin" OR "estecina" OR "felixene" OR "fimoflox" OR "flociprin" OR "flontalexin" OR "floroxin" OR "floxager" OR "floxantina" OR "floxbio" OR "fonterra" OR "generflon" OR "gerbat" OR "ginorectol" OR "giroflox" OR "gonning" OR "grifociprox" OR "h-next" OR "holdestin" OR "ibixacin" OR "inciflox" OR "infectocipro" OR "inkamil" OR "iprolan" OR "isotic" OR "jayacin" OR "k-sacin" OR "kenzoflex" OR "kinoves" OR "kinox" OR "kipocin" OR "labentrol" OR "ladinin" OR "limox" OR "linhaliq" OR "lipoquin" OR "lofucin" OR "loxan" OR "macar" OR "medociprin" OR "mitroken" OR "nafloxin" OR "neofloxin" OR "nivoflox" OR "novidat" OR "novoquin" OR "oftacilox" OR "opthaflox" OR "otanol" OR "otiprio" OR "otociprin" OR "otosec" OR "phaproxin" OR "pharcina" OR "poncoflox" OR "probiox" OR "prociflor" OR "procin" OR "proflaxin" OR "profloxin" OR "proksi 250" OR "proksi 500" OR "proquin" OR "proxacin" OR "pulmaquin" OR "qilaflox" OR "qinosyn" OR "quilox" OR "quinobiotic" OR "quinoflox" OR "quinolide" OR "quinox" OR "quintor" OR "qupron" OR "rancif" OR "ravalton" OR "revionorm" OR "rigoran" OR "rofcin" OR "roflazin" OR "rosacin eye drop" OR "samper" OR "sarf" OR "sepcen" OR "septicide" OR "septocipro" OR "sifloks" OR "siprogut" OR "siprox" OR "sophixin ofteno" OR "spitacin" OR "strox" OR "suiflox" OR "superocin" OR "syntoflox" OR "topistin" OR "truoxin" OR "ufexil" OR "ullax" OR "unex" OR "unicexal" OR "uniflox" OR "urodixin" OR "uroxin" OR "viprolox" OR "zindolin" OR "zipra" OR "zumaflox" OR

"Levofloxacin*" OR ("(S)-isomer" W/3 "Ofloxacin") OR "Quixin" OR "Levaquin" OR "aeroquin" OR "cravit" OR "elequine" OR "eyflox" OR "floxacin" OR "floxel" OR "iquix" OR "leroxacin" OR "lesacin" OR "levokacin" OR "levox" OR "levoxacin" OR "mosardal" OR "nofaxin" OR "oftaquix" OR "oxalux" OR "prixar" OR "quinsair" OR "reskuin" OR "supraflox" OR "tavanic" OR "unibiotic" OR "venaxan" OR "volequin" OR

"ofloxacin*" OR "tarivid" OR "akilen" OR "audret" OR "bactocin" OR "bioquil" OR "danoflox" OR "effexin" OR "eukinoft" OR "exocin" OR "exocine" OR "flobacin" OR "flodemex" OR "flotavid" OR "flovid" OR "floxal" OR "floxedol" OR "floxigen" OR "floxil" OR "floxin" OR "floxstat" OR "fugacin" OR "grenis-oflo" OR "gyroflox" OR "inoflox" OR "kinflocin" OR "kinoxacin" OR "liflox" OR "loxinter" OR "marfloxacin" OR "medofloxin" OR "medofloxine"

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OR "mergexin" OR "monoflocet" OR "monoox" OR "novecin" OR "nufafloqo" OR "o-flox" OR "obide" OR "occidal" OR "ocuflox" OR "ofcin" OR "oflin" OR "oflocee" OR "oflocet" OR "oflocin" OR "oflodal" OR "oflodex" OR "oflodinex" OR "oflodura" OR "oflogen" OR "oflohexal" OR "oflovir" OR "oflox" OR "ofloxa-vision" OR "ofloxacino" OR "ofloxamed" OR "ofloxavis" OR "ofloxin" OR "ofus" OR "onexacin" OR "operan" OR "orocin" OR "otiflox" OR "otonil" OR "ottoflox" OR "oxacid" OR "oxatrex" OR "pharflox" OR "praxin" OR "puiritol" OR "qinolon" OR "qipro" OR "quinofree" OR "quinolon" OR "quotavil" OR "rilox" OR "romacin" OR "sinflo" OR "surnox" OR "tabrin" OR "taravid" OR "tariflox" OR "taroflox" OR "telbit" OR "trafloxal" OR "tructum" OR "urotarivid" OR "viotisone" OR "visuab" OR "zanocin" OR

"Moxifloxacin*" OR "Octegra" OR "Proflox" OR "Avelox" OR "Avalox" OR "Izilox" OR "Actira" OR "avelon" OR "bacterol" OR "floxamic" OR "floxitrat" OR "izilox" OR "kanavig" OR "lifodrox" OR "megaxin" OR "melocin" OR "moksacin" OR "monafox" OR "moxeza" OR "moxibay" OR "moxif" OR "moxivig" OR "octegra" OR "proflox" OR "tamvelier" OR "vamocin" OR "vegamox" OR "vigamox" OR "vigamoxi" OR "xiflodrop" OR "zimoxin" OR

"penicillin*" OR

"Amoxicillin*" OR "Amoxycillin*" OR "Hydroxyampicillin" OR "Actimoxi" OR "Clamoxyl" OR "Penamox" OR "Polymox" OR "Trimox" OR "Wymox" OR "Amoxil" OR "a gram" OR "abdimox" OR "acilina" OR "acimox" OR "adbiotin" OR "agerpen" OR "agram" OR "alfamox" OR "alfoxil" OR "almodan" OR "almorsan" OR "alphamox" OR "amagesen solutab" OR "ameclina" OR "amitron" OR "amo-flamisan" OR "amo-flamsian" OR "amocillin" OR "amoclen" OR "amodex" OR "amoflux" OR "amohexal" OR "amolin" OR "amonex" OR "amopen" OR "amophar ge" OR "amosine" OR "amoval" OR "amoxa" OR "amoxal" OR "amoxapen" OR "amoxaren" OR "amoxcil" OR "amoxcillin" OR "amoxcin" OR "amoxi-basan" OR "amoxicilina" OR "amoxiclin" OR "amoxicot" OR "amoxidal" OR "amoxidin" OR "amoxidrops" OR "amoxihexal" OR "amoxillin" OR "amoxina" OR "amoxipen" OR "amoxipenil" OR "amoxisol" OR "amoxivan" OR "amoxivet" OR "amoxy" OR "amoxy-diolan" OR "amoxypen" OR "ampliron" OR "apo-amoxi" OR "ardine" OR "aroxin" OR "azillin" OR "bacihexal" OR "bactamox" OR "bactox ge" OR "beamoxy" OR "betamox" OR "bimox" OR "bintamox" OR "biomox" OR "biotamoxal" OR "bioxidona" OR "bioxyllin" OR "bristamox" OR "broadmetz" OR "cabermox" OR "cilamox" OR "clamox" OR "clearamox" OR "clonamox" OR "coamoxin" OR "damoxicil" OR "dispermox" OR "doxamil" OR "draximox" OR "edamox" OR "efpinex" OR "erphamoxy" OR "eupen" OR "farconcil" OR "fisamox" OR "flemoxin" OR "flemoxine ge" OR "fluamoxina" OR "foxolin" OR "fullcilina" OR "gexcil" OR "gimalxina" OR "glamox" OR "glassatan" OR "gomcillin" OR "grinsul" OR "grunamox" OR "hamoxillin" OR "hiconcil" OR "hidramox" OR "hipen" OR "hosboral" OR "ibamox" OR "ibiamox" OR "ikamoxil" OR "imacillin" OR "imaxilin" OR "inamox" OR "infectomycin" OR "intermox" OR "isimoxin" OR "izoltil" OR "julphamox" OR "jutamox" OR "kamoxin" OR "ladoxillin" OR "lamoxy" OR "larocilin" OR "larocin" OR "larotid" OR "macromox" OR "magnimox" OR "maxamox" OR "maxcil" OR "medimox" OR "meixil" OR "metifarma" OR "mopen" OR "morgenxil" OR "moxacin" OR "moxaline" OR "moxarin" OR "moxatag" OR "moxilen" OR "moxilin" OR "moximar" OR "moxitab" OR "moxtid" OR "moxylin" OR "moxypen" OR "moxyvit" OR "neogram" OR "novabritine" OR "novamox" OR "novamoxin" OR "novenzymin" OR "novoxil" OR "nuvosyl" OR "optium" OR "oramox" OR "ospamox" OR "pamocil" OR "pamoxicillin" OR "pamoxin" OR "panvilon" OR "pasetocin" OR "penbiosyn" OR "pentyloxycillin" OR "pharmoxyl" OR "piramox" OR "pondnoxcill" OR "rancil" OR "ranmoxy" OR "ranoxil" OR "ranoxyl" OR "robamox" OR "romoxil" OR "ronemox" OR "saltermox" OR "sawacillin" OR "sawamezin" OR "servamox" OR "shamoxil" OR "sia-mox" OR "sigamopen" OR "sil-a-mox" OR "silamox" OR "simoxil" OR "sintopen" OR "solamocta" OR "solpenox" OR "sumox" OR "superpeni" OR "teramoxyl" OR "tolodina" OR "tormoxin" OR "triafamox" OR

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"triamoxil" OR "trifamox" OR "uro clamoxyl" OR "uroclamoxyl" OR "utimox" OR "vastamox" OR "velamox" OR "vistrep" OR "widecillin" OR "winpen" OR "xiltrop" OR "zamocillin" OR "zamox" OR "zamoxil" OR "zerrsox" OR "zimox" OR

"Co-amoxiclav" OR "Coamoxiclav" OR "Amoxi-Clavulanate" OR "Amox-clav" OR "Synulox" OR "Spektramox" OR "Augmentin" OR "Clavulin" OR "aclam" OR "aktil" OR "ambilan" OR "amocla" OR "amoclan" OR "amoclane" OR "amoclav" OR "amoksiklav" OR "amolanic" OR "amometin" OR "amoxi plus" OR "amoxiclav" OR "amoxiclav-bid" OR "amoxiclav-teva" OR "amoxsiklav" OR "amoxxlin" OR "ancla" OR "auclatin duo dry syrup" OR "augamox" OR "augmaxcil" OR "augmentan" OR "augmentine" OR "augmex" OR "augpen" OR "augucillin duo" OR "augurcin" OR "ausclav" OR "auspilic" OR "bactiv" OR "bactoclav" OR "bioclavid" OR "cavumox" OR "ciblor" OR "clacillin duo dry syrup" OR "clamax" OR "clamentin" OR "clamobit" OR "clamonex" OR "clamovid" OR "clamoxin" OR "clamoxyl duo 400" OR "clamoxyl duoforte" OR "clarin-duo" OR "clavam" OR "clavamox" OR "clavar" OR "clavinex" OR "clavodar" OR "clavoxil" OR "clavoxilin plus" OR "clavubactin" OR "clavucid" OR "clavudale" OR "clavulox duo" OR "clavumox" OR "co amoxyclav" OR "coamoxyclav" OR "cramon duo" OR "croanan duo dry syrup" OR "curam" OR "danoclav" OR "darzitil plus" OR "duamentin" OR "duomox" OR "e-moxclav" OR "enhancin" OR "eumetinex" OR "fleming" OR "forcid" OR "forcid solutab" OR "fugentin" OR "fullicilina plus" OR "gumentin" OR "hibiotic" OR "inciclav" OR "klamonex" OR "kmoxilin" OR "lactamox" OR "lansiclav" OR "moxiclav" OR "moxicle" OR "moxyclav" OR "natravox" OR "neoduplamox" OR "noprilam" OR "nufaclav" OR "omep plus" OR "palentin" OR "quali-mentin" OR "ranclav" OR "spectramox" OR "stacillin" OR "strenzen" OR "suplentin" OR "synermox" OR "taromentin" OR "taromentin es" OR "velamox cl" OR "vestaclav" OR "viaclav" OR "vulamox" OR "xiclav" OR "zami 8503" OR

"floxacillin*" OR "Fluorochloroxacillin" OR "Flucloxacillin" OR "flopen" OR "floxapen" OR "flucil" OR "heracillin" OR "stafoxil" OR "staphylex" OR

"Tetracyclin*" OR

"Doxycyclin*" OR "Vibramycin*" OR "Atridox" OR "Doryx" OR "Hydramycin" OR "Oracea" OR "Periostat" OR "Vibra-Tabs" OR "Vibravenos" OR "adoxa" OR "amermycin" OR "apprilon" OR "atrax" OR "azudoxat" OR "bactidox" OR "banndoclin" OR "basedillin" OR "bassado" OR "biocolyn" OR "biodoxi" OR "bronmycin" OR "cloran" OR "cyclidox" OR "dentistar" OR "deoxycycline" OR "deoxymycin dispersal" OR "deoxymykoin" OR "deoxyoxytetracycline" OR "desoxy oxytetracycline" OR "desoxycycline" OR "doinmycin" OR "dosil" OR "dotur" OR "doxaciclin" OR "doxacycline" OR "doxat" OR "doxatet" OR "doxi -sergo" OR "doxibiotic" OR "doxicycline" OR "doxilin" OR "doximed" OR "doximycin" OR "doxin" OR "doxine" OR "doxirobe" OR "doxocycline" OR "doxsig" OR "doxy" OR "doxybiocin" OR "doxycen" OR "doxychel" OR "doxycin" OR "doxylag" OR "doxylin" OR "doxymycin" OR "doxypuren" OR "doxytec" OR "doxytrim" OR "dumoxin" OR "duracycline" OR "efracea" OR "esdoxin" OR "etidoxina" OR "gewacyclin" OR "ibralene" OR "idocyclin" OR "idocyklin" OR "interdoxin" OR "investin" OR "longamycin" OR "lydox" OR "magdrin" OR "medomycin" OR "mespafin" OR "mildox" OR "miraclin" OR "monodox" OR "nanodox" OR "nordox" OR "oraycea" OR "paldomycin" OR "pernox gel" OR "radox" OR "remycin" OR "respidox" OR "roximycin" OR "serodoxy" OR "servidoxine" OR "servidoxyne" OR "siadocin" OR "siclidon" OR "sigadoxin" OR "spanor" OR "supracyclin" OR "supramycina" OR "tenutan" OR "tolexine" OR "torymycin" OR "tsurupioxin" OR "unidox" OR "veemycin" OR "viadoxin" OR "vibra s" OR "vibra-s" OR "vibrabiotic" OR "vibracina" OR "vibradox" OR "vibramicina" OR "vibraveineuse" OR "vibravet" OR "viradoxyl-n" OR "wanmycin" OR "xyrosa" OR "zadorin" OR "zenavod" OR

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"Minocyclin*" OR "Minox 50" OR "Aknemin" OR "Aknin-Mino" OR "Aknosan" OR "Mynocine" OR "Arestin" OR "Blemix" OR "Cyclomin" OR "Cyclops" OR "Dentomycin" OR "Dynacin" OR "Icht-Oral" OR "Klinomycin" OR "Lederderm" OR "Mestacine" OR "Minakne" OR "MinoWolff" OR "Minocin" OR "Minoclir" OR "Minolis" OR "Minomycin" OR "Minoplus" OR "Minotab" OR "Akamin" OR "Akne-Puren" OR "amzeeq" OR "borymycin" OR "cipancin" OR "cyclimycin" OR "cynomycin" OR "klinotab" OR "kyno" OR "logryx" OR "menocycline" OR "micromycin" OR "minaxen" OR "mino-50" OR "minoclin" OR "minocyn" OR "minogalen" OR "minoline" OR "minolira" OR "minomax" OR "minosil" OR "minostad" OR "minotrex" OR "minoz ep" OR "mirosin" OR "parocline" OR "periofeel" OR "romin" OR "sebomir" OR "skinocyclin" OR "solodyn" OR "spicline" OR "vectran" OR "vectrin" OR "ximino" OR "zilxi" OR

"sulfanilamide*" OR "sulfonamide*" OR "sulphanilamide*" OR "sulphonamide*" OR

"Centrin" OR "Cotrimoxazole" OR "Co-Trimoxazole" OR "Eslectin" OR "Insozalin" OR "Trimezol*" OR "Centran" OR "Trimedin" OR "Septrin*" OR "Bactifor" OR "Sumetrolim" OR "Abactrim" OR "Bactrim" OR "Biseptol" OR "Biseptol480" OR "Drylin" OR "Eusaprim" OR "Kepinol" OR "Lescot" OR "Metomide" OR "Oriprim" OR "Septra" OR "Sulprim" OR "Trimosulfa" OR "abactrin" OR "alfatrim" OR "apo sulfatrim" OR "bactar" OR "bactipront" OR "bactoreduct forte" OR "bactramin" OR "bactrimel" OR "bethaprim" OR "bispetol" OR "chemotrim" OR "comox" OR "comoxol" OR "cotrim" OR "cotrimoxazol forte" OR "cotrimstada forte" OR "deprim" OR "deprim forte" OR "duobact" OR "duobiocin" OR "duobiocin forte" OR "duratrimet" OR "eltrianyl" OR "escoprim" OR "espectrin" OR "fectrim" OR "groprim" OR "helveprim" OR "imexim" OR "infectrim" OR "lagaprim" OR "lagatrim" OR "linaris" OR "microtrim" OR "neoprim" OR "nopil" OR "oecotrim" OR "omsat" OR "oribact" OR "pharmaprim" OR "potesept" OR "resprim" OR "resprin" OR "scanprin" OR "septran" OR "septrim" OR "sigaprim" OR "sinersol" OR "soltrim" OR "sulfamethoprim" OR "sulfaprim" OR "sulfatrim" OR "sulfotrim" OR "sulmeprim" OR "sumetrolin" OR "supracombin" OR "thiocuran" OR "tms forte" OR "trib" OR "trigonyl" OR "trimeth/sulfa" OR "trimetoprim-sulfa" OR "trimetoprimsulfamethoxazole" OR "trimforte" OR "trimoxazole" OR "trimoxol" OR "uro ts d" OR "uroplus ds" OR "uroplus ss" OR

"pyrimidin*" OR

"trimethoprim*" OR "trimpex" OR "proloprim" OR "abaprim" OR "alprim" OR "catin" OR "delprim" OR "giprim" OR "idotrim" OR "infectotrimet" OR "methoprim" OR "monoprim" OR "monotrim" OR "motrim" OR "primosept" OR "primsol" OR "solotrim" OR "syraprim" OR "tiempe" OR "tmp-ratiopharm" OR "tobyprim" OR "trimesan" OR "trimethoprin" OR "trimetoprim" OR "trimfect" OR "trimono" OR "trimopan" OR "trinopan" OR "triprim" OR "trisul" OR "uretrim" OR "utisept" OR "welcoprim" OR "wellcoprim" OR

"Cephalosporin*" OR "cefalosporin*" OR

"Cefuroxim*" OR "Cephuroxim*" OR "Zinacef" OR "Ketocef" OR "aksef" OR "alporin" OR "altacef" OR "anaptivan" OR "aprok" OR "aprokam" OR "biocefal" OR "cefoxurime" OR "cefumax" OR "ceplus" OR "ceroxime" OR "curocef" OR "curoxim" OR "curoxima" OR "curoxime" OR "eroxmit" OR "froxal" OR "fucerox" OR "furoxime" OR "iceca" OR "intracef" OR "kefazol" OR "kefurim" OR "kefurox" OR "kesint" OR "laxinat" OR "maxil" OR "normafenac" OR "polixima" OR "prokam" OR "supacef" OR "tarsime" OR "ucefaxim" OR "ultroxim" OR "uroxime" OR "vekfazolin" OR "ximaract" OR "zinocef") OR

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AUTHKEY("anti-bacterial" OR "antibacterial" OR "Bacteriocid*" OR "anti-mycobacterial" OR "antimycobacterial" OR "antibiotic*" OR

"fluoroquinolon*" OR "quinolon*" OR "chinolon*" OR "quinolin*" OR "chinolin*" OR

"cipro*" OR "ciprinol" OR "aceoto" OR "acire" OR "alcon cilox" OR "apulmiq" OR "araxacina" OR "aristin-c" OR "auripro" OR "bacquinor" OR "bactiflox" OR "baflox" OR "basemar" OR "battizer" OR "baycip" OR "bernoflox" OR "bivorilan" OR "bosix" OR "c-flox" OR "c-floxacin" OR "catex" OR "cetraflux" OR "cetraxal" OR "chinocid" OR "cidroxal" OR "cifin" OR "ciflan" OR "ciflo" OR "ciflosin" OR "ciflot" OR "ciflox" OR "cifloxin" OR "cifox" OR "cifran" OR "cilab" OR "ciloquin" OR "ciloxan" OR "ciloxin" OR "cimogal" OR "cinaflox" OR "cipad" OR "ciperus" OR "cipflox" OR "ciphin" OR "cipide" OR "cipio" OR "ciplox" OR "ciplus" OR "cipocin" OR "ciprecu" OR "ciriax" OR "cirok" OR "cirokan" OR "cirox" OR "ciroxin" OR "citopcin" OR "citrovenot" OR "cobay" OR "corsacin" OR "cosflox" OR "cuminol" OR "cuspis" OR "cycin" OR "cyfloxin" OR "cypral" OR "cyprobay" OR "cysfec" OR "doriman" OR "droll" OR "eoxin" OR "eprocin" OR "estecina" OR "felixene" OR "fimoflox" OR "flociprin" OR "flontalexin" OR "floroxin" OR "floxager" OR "floxantina" OR "floxbio" OR "fonterra" OR "generflon" OR "gerbat" OR "ginorectol" OR "giroflox" OR "gonning" OR "grifociprox" OR "h-next" OR "holdestin" OR "ibixacin" OR "inciflox" OR "infectocipro" OR "inkamil" OR "iprolan" OR "isotic" OR "jayacin" OR "k-sacin" OR "kenzoflex" OR "kinoves" OR "kinox" OR "kipocin" OR "labentrol" OR "ladinin" OR "limox" OR "linhaliq" OR "lipoquin" OR "lofucin" OR "loxan" OR "macar" OR "medociprin" OR "mitroken" OR "nafloxin" OR "neofloxin" OR "nivoflox" OR "novidat" OR "novoquin" OR "oftacilox" OR "opthaflox" OR "otanol" OR "otiprio" OR "otociprin" OR "otosec" OR "phaproxin" OR "pharcina" OR "poncoflox" OR "probiox" OR "prociflor" OR "procin" OR "proflaxin" OR "profloxin" OR "proksi 250" OR "proksi 500" OR "proquin" OR "proxacin" OR "pulmaquin" OR "qilaflox" OR "qinosyn" OR "quilox" OR "quinobiotic" OR "quinoflox" OR "quinolide" OR "quinox" OR "quintor" OR "qupron" OR "rancif" OR "ravalton" OR "revionorm" OR "rigoran" OR "rofcin" OR "roflazin" OR "rosacin eye drop" OR "samper" OR "sarf" OR "sepcen" OR "septicide" OR "septocipro" OR "sifloks" OR "siprogut" OR "siprox" OR "sophixin ofteno" OR "spitacin" OR "strox" OR "suiflox" OR "superocin" OR "syntoflox" OR "topistin" OR "truoxin" OR "ufexil" OR "ullax" OR "unex" OR "unicexal" OR "uniflox" OR "urodixin" OR "uroxin" OR "viprolox" OR "zindolin" OR "zipra" OR "zumaflox" OR

"Levofloxacin*" OR ("(S)-isomer" W/3 "Ofloxacin") OR "Quixin" OR "Levaquin" OR "aeroquin" OR "cravit" OR "elequine" OR "eyflox" OR "floxacin" OR "floxel" OR "iquix" OR "leroxacin" OR "lesacin" OR "levokacin" OR "levox" OR "levoxacin" OR "mosardal" OR "nofaxin" OR "oftaquix" OR "oxalux" OR "prixar" OR "quinsair" OR "reskuin" OR "supraflox" OR "tavanic" OR "unibiotic" OR "venaxan" OR "volequin" OR

"ofloxacin*" OR "tarivid" OR "akilen" OR "audret" OR "bactocin" OR "bioquil" OR "danoflox" OR "effexin" OR "eukinoft" OR "exocin" OR "exocine" OR "flobacin" OR "flodemex" OR "flotavid" OR "flovid" OR "floxal" OR "floxedol" OR "floxigen" OR "floxil" OR "floxin" OR "floxstat" OR "fugacin" OR "grenis-oflo" OR "gyroflox" OR "inoflox" OR "kinflocin" OR "kinoxacin" OR "liflox" OR "loxinter" OR "marfloxacin" OR "medofloxin" OR "medofloxine" OR "mergexin" OR "monoflocet" OR "monoox" OR "novecin" OR "nufafloqo" OR "o-flox" OR "obide" OR "occidal" OR "ocuflox" OR "ofcin" OR "oflin" OR "oflocee" OR "oflocet" OR "oflocin" OR "oflodal" OR "oflodex" OR "oflodinex" OR "oflodura" OR "oflogen" OR "oflohexal" OR "oflovir" OR "oflox" OR "ofloxa-vision" OR "ofloxacino" OR "ofloxamed" OR "ofloxavis" OR "ofloxin" OR "ofus" OR "onexacin" OR "operan" OR "orocin" OR "otiflox" OR "otonil" OR "ottoflox" OR "oxacid" OR "oxatrex" OR "pharflox" OR "praxin" OR "puiritol" OR

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"qinolon" OR "qipro" OR "quinofree" OR "quinolon" OR "quotavil" OR "rilox" OR "romacin" OR "sinflo" OR "surnox" OR "tabrin" OR "taravid" OR "tariflox" OR "taroflox" OR "telbit" OR "trafloxal" OR "tructum" OR "urotarivid" OR "viotisone" OR "visuab" OR "zanocin" OR

"Moxifloxacin*" OR "Octegra" OR "Proflox" OR "Avelox" OR "Avalox" OR "Izilox" OR "Actira" OR "avelon" OR "bacterol" OR "floxamic" OR "floxitrat" OR "izilox" OR "kanavig" OR "lifodrox" OR "megaxin" OR "melocin" OR "moksacin" OR "monafox" OR "moxeza" OR "moxibay" OR "moxif" OR "moxivig" OR "octegra" OR "proflox" OR "tamvelier" OR "vamocin" OR "vegamox" OR "vigamox" OR "vigamoxi" OR "xiflodrop" OR "zimoxin" OR

"penicillin*" OR

"Amoxicillin*" OR "Amoxycillin*" OR "Hydroxyampicillin" OR "Actimoxi" OR "Clamoxyl" OR "Penamox" OR "Polymox" OR "Trimox" OR "Wymox" OR "Amoxil" OR "a gram" OR "abdimox" OR "acilina" OR "acimox" OR "adbiotin" OR "agerpen" OR "agram" OR "alfamox" OR "alfoxil" OR "almodan" OR "almorsan" OR "alphamox" OR "amagesen solutab" OR "ameclina" OR "amitron" OR "amo-flamisan" OR "amo-flamsian" OR "amocillin" OR "amoclen" OR "amodex" OR "amoflux" OR "amohexal" OR "amolin" OR "amonex" OR "amopen" OR "amophar ge" OR "amosine" OR "amoval" OR "amoxa" OR "amoxal" OR "amoxapen" OR "amoxaren" OR "amoxcil" OR "amoxcillin" OR "amoxcin" OR "amoxi-basan" OR "amoxicilina" OR "amoxiclin" OR "amoxicot" OR "amoxidal" OR "amoxidin" OR "amoxidrops" OR "amoxihexal" OR "amoxillin" OR "amoxina" OR "amoxipen" OR "amoxipenil" OR "amoxisol" OR "amoxivan" OR "amoxivet" OR "amoxy" OR "amoxy-diolan" OR "amoxypen" OR "ampliron" OR "apo-amoxi" OR "ardine" OR "aroxin" OR "azillin" OR "bacihexal" OR "bactamox" OR "bactox ge" OR "beamoxy" OR "betamox" OR "bimox" OR "bintamox" OR "biomox" OR "biotamoxal" OR "bioxidona" OR "bioxyllin" OR "bristamox" OR "broadmetz" OR "cabermox" OR "cilamox" OR "clamox" OR "clearamox" OR "clonamox" OR "coamoxin" OR "damoxicil" OR "dispermox" OR "doxamil" OR "draximox" OR "edamox" OR "efpinex" OR "erphamoxy" OR "eupen" OR "farconcil" OR "fisamox" OR "flemoxin" OR "flemoxine ge" OR "fluamoxina" OR "foxolin" OR "fullcilina" OR "gexcil" OR "gimalxina" OR "glamox" OR "glassatan" OR "gomcillin" OR "grinsul" OR "grunamox" OR "hamoxillin" OR "hiconcil" OR "hidramox" OR "hipen" OR "hosboral" OR "ibamox" OR "ibiamox" OR "ikamoxil" OR "imacillin" OR "imaxilin" OR "inamox" OR "infectomycin" OR "intermox" OR "isimoxin" OR "izoltil" OR "julphamox" OR "jutamox" OR "kamoxin" OR "ladoxillin" OR "lamoxy" OR "larocilin" OR "larocin" OR "larotid" OR "macromox" OR "magnimox" OR "maxamox" OR "maxcil" OR "medimox" OR "meixil" OR "metifarma" OR "mopen" OR "morgenxil" OR "moxacin" OR "moxaline" OR "moxarin" OR "moxatag" OR "moxilen" OR "moxilin" OR "moximar" OR "moxitab" OR "moxtid" OR "moxylin" OR "moxypen" OR "moxyvit" OR "neogram" OR "novabritine" OR "novamox" OR "novamoxin" OR "novenzymin" OR "novoxil" OR "nuvosyl" OR "optium" OR "oramox" OR "ospamox" OR "pamocil" OR "pamoxicillin" OR "pamoxin" OR "panvilon" OR "pasetocin" OR "penbiosyn" OR "pentyloxycillin" OR "pharmoxyl" OR "piramox" OR "pondnoxcill" OR "rancil" OR "ranmoxy" OR "ranoxil" OR "ranoxyl" OR "robamox" OR "romoxil" OR "ronemox" OR "saltermox" OR "sawacillin" OR "sawamezin" OR "servamox" OR "shamoxil" OR "sia-mox" OR "sigamopen" OR "sil-a-mox" OR "silamox" OR "simoxil" OR "sintopen" OR "solamocta" OR "solpenox" OR "sumox" OR "superpeni" OR "teramoxyl" OR "tolodina" OR "tormoxin" OR "triafamox" OR "triamoxil" OR "trifamox" OR "uro clamoxyl" OR "uroclamoxyl" OR "utimox" OR "vastamox" OR "velamox" OR "vistrep" OR "widecillin" OR "winpen" OR "xiltrop" OR "zamocillin" OR "zamox" OR "zamoxil" OR "zerrsox" OR "zimox" OR

"Co-amoxiclav" OR "Coamoxiclav" OR "Amoxi-Clavulanate" OR "Amox-clav" OR "Synulox" OR "Spektramox" OR "Augmentin" OR "Clavulin" OR "aclam" OR "aktil" OR "ambilan" OR

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"amocla" OR "amoclan" OR "amoclane" OR "amoclav" OR "amoksiklav" OR "amolanic" OR "amometin" OR "amoxi plus" OR "amoxiclav" OR "amoxiclav-bid" OR "amoxiclav-teva" OR "amoxsiklav" OR "amoxxlin" OR "ancla" OR "auclatin duo dry syrup" OR "augamox" OR "augmaxcil" OR "augmentan" OR "augmentine" OR "augmex" OR "augpen" OR "augucillin duo" OR "augurcin" OR "ausclav" OR "auspilic" OR "bactiv" OR "bactoclav" OR "bioclavid" OR "cavumox" OR "ciblor" OR "clacillin duo dry syrup" OR "clamax" OR "clamentin" OR "clamobit" OR "clamonex" OR "clamovid" OR "clamoxin" OR "clamoxyl duo 400" OR "clamoxyl duoforte" OR "clarin-duo" OR "clavam" OR "clavamox" OR "clavar" OR "clavinex" OR "clavodar" OR "clavoxil" OR "clavoxilin plus" OR "clavubactin" OR "clavucid" OR "clavudale" OR "clavulox duo" OR "clavumox" OR "co amoxyclav" OR "coamoxyclav" OR "cramon duo" OR "croanan duo dry syrup" OR "curam" OR "danoclav" OR "darzitil plus" OR "duamentin" OR "duomox" OR "e-moxclav" OR "enhancin" OR "eumetinex" OR "fleming" OR "forcid" OR "forcid solutab" OR "fugentin" OR "fullicilina plus" OR "gumentin" OR "hibiotic" OR "inciclav" OR "klamonex" OR "kmoxilin" OR "lactamox" OR "lansiclav" OR "moxiclav" OR "moxicle" OR "moxyclav" OR "natravox" OR "neoduplamox" OR "noprilam" OR "nufaclav" OR "omep plus" OR "palentin" OR "quali-mentin" OR "ranclav" OR "spectramox" OR "stacillin" OR "strenzen" OR "suplentin" OR "synermox" OR "taromentin" OR "taromentin es" OR "velamox cl" OR "vestaclav" OR "viaclav" OR "vulamox" OR "xiclav" OR "zami 8503" OR

"floxacillin*" OR "Fluorochloroxacillin" OR "Flucloxacillin" OR "flopen" OR "floxapen" OR "flucil" OR "heracillin" OR "stafoxil" OR "staphylex" OR

"Tetracyclin*" OR

"Doxycyclin*" OR "Vibramycin*" OR "Atridox" OR "Doryx" OR "Hydramycin" OR "Oracea" OR "Periostat" OR "Vibra-Tabs" OR "Vibravenos" OR "adoxa" OR "amermycin" OR "apprilon" OR "atrax" OR "azudoxat" OR "bactidox" OR "banndoclin" OR "basedillin" OR "bassado" OR "biocolyn" OR "biodoxi" OR "bronmycin" OR "cloran" OR "cyclidox" OR "dentistar" OR "deoxycycline" OR "deoxymycin dispersal" OR "deoxymykoin" OR "deoxyoxytetracycline" OR "desoxy oxytetracycline" OR "desoxycycline" OR "doinmycin" OR "dosil" OR "dotur" OR "doxaciclin" OR "doxacycline" OR "doxat" OR "doxatet" OR "doxi -sergo" OR "doxibiotic" OR "doxicycline" OR "doxilin" OR "doximed" OR "doximycin" OR "doxin" OR "doxine" OR "doxirobe" OR "doxocycline" OR "doxsig" OR "doxy" OR "doxybiocin" OR "doxycen" OR "doxychel" OR "doxycin" OR "doxylag" OR "doxylin" OR "doxymycin" OR "doxypuren" OR "doxytec" OR "doxytrim" OR "dumoxin" OR "duracycline" OR "efracea" OR "esdoxin" OR "etidoxina" OR "gewacyclin" OR "ibralene" OR "idocyclin" OR "idocyklin" OR "interdoxin" OR "investin" OR "longamycin" OR "lydox" OR "magdrin" OR "medomycin" OR "mespafin" OR "mildox" OR "miraclin" OR "monodox" OR "nanodox" OR "nordox" OR "oraycea" OR "paldomycin" OR "pernox gel" OR "radox" OR "remycin" OR "respidox" OR "roximycin" OR "serodoxy" OR "servidoxine" OR "servidoxyne" OR "siadocin" OR "siclidon" OR "sigadoxin" OR "spanor" OR "supracyclin" OR "supramycina" OR "tenutan" OR "tolexine" OR "torymycin" OR "tsurupioxin" OR "unidox" OR "veemycin" OR "viadoxin" OR "vibra s" OR "vibra-s" OR "vibrabiotic" OR "vibracina" OR "vibradox" OR "vibramicina" OR "vibraveineuse" OR "vibravet" OR "viradoxyl-n" OR "wanmycin" OR "xyrosa" OR "zadorin" OR "zenavod" OR

"Minocyclin*" OR "Minox 50" OR "Aknemin" OR "Aknin-Mino" OR "Aknosan" OR "Mynocine" OR "Arestin" OR "Blemix" OR "Cyclomin" OR "Cyclops" OR "Dentomycin" OR "Dynacin" OR "Icht-Oral" OR "Klinomycin" OR "Lederderm" OR "Mestacine" OR "Minakne" OR "MinoWolff" OR "Minocin" OR "Minoclir" OR "Minolis" OR "Minomycin" OR "Minoplus" OR "Minotab" OR "Akamin" OR "Akne-Puren" OR "amzeeq" OR "borymycin" OR "cipancin" OR

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"cyclimycin" OR "cynomycin" OR "klinotab" OR "kyno" OR "logryx" OR "menocycline" OR "micromycin" OR "minaxen" OR "mino-50" OR "minoclin" OR "minocyn" OR "minogalen" OR "minoline" OR "minolira" OR "minomax" OR "minosil" OR "minostad" OR "minotrex" OR "minoz ep" OR "mirosin" OR "parocline" OR "periofeel" OR "romin" OR "sebomir" OR "skinocyclin" OR "solodyn" OR "spicline" OR "vectran" OR "vectrin" OR "ximino" OR "zilxi" OR

"sulfanilamide*" OR "sulfonamide*" OR "sulphanilamide*" OR "sulphonamide*" OR

"Centrin" OR "Cotrimoxazole" OR "Co-Trimoxazole" OR "Eslectin" OR "Insozalin" OR "Trimezol*" OR "Centran" OR "Trimedin" OR "Septrin*" OR "Bactifor" OR "Sumetrolim" OR "Abactrim" OR "Bactrim" OR "Biseptol" OR "Biseptol480" OR "Drylin" OR "Eusaprim" OR "Kepinol" OR "Lescot" OR "Metomide" OR "Oriprim" OR "Septra" OR "Sulprim" OR "Trimosulfa" OR "abactrin" OR "alfatrim" OR "apo sulfatrim" OR "bactar" OR "bactipront" OR "bactoreduct forte" OR "bactramin" OR "bactrimel" OR "bethaprim" OR "bispetol" OR "chemotrim" OR "comox" OR "comoxol" OR "cotrim" OR "cotrimoxazol forte" OR "cotrimstada forte" OR "deprim" OR "deprim forte" OR "duobact" OR "duobiocin" OR "duobiocin forte" OR "duratrimet" OR "eltrianyl" OR "escoprim" OR "espectrin" OR "fectrim" OR "groprim" OR "helveprim" OR "imexim" OR "infectrim" OR "lagaprim" OR "lagatrim" OR "linaris" OR "microtrim" OR "neoprim" OR "nopil" OR "oecotrim" OR "omsat" OR "oribact" OR "pharmaprim" OR "potesept" OR "resprim" OR "resprin" OR "scanprin" OR "septran" OR "septrim" OR "sigaprim" OR "sinersol" OR "soltrim" OR "sulfamethoprim" OR "sulfaprim" OR "sulfatrim" OR "sulfotrim" OR "sulmeprim" OR "sumetrolin" OR "supracombin" OR "thiocuran" OR "tms forte" OR "trib" OR "trigonyl" OR "trimeth/sulfa" OR "trimetoprim-sulfa" OR "trimetoprimsulfamethoxazole" OR "trimforte" OR "trimoxazole" OR "trimoxol" OR "uro ts d" OR "uroplus ds" OR "uroplus ss" OR

"pyrimidin*" OR

"trimethoprim*" OR "trimpex" OR "proloprim" OR "abaprim" OR "alprim" OR "catin" OR "delprim" OR "giprim" OR "idotrim" OR "infectotrimet" OR "methoprim" OR "monoprim" OR "monotrim" OR "motrim" OR "primosept" OR "primsol" OR "solotrim" OR "syraprim" OR "tiempe" OR "tmp-ratiopharm" OR "tobyprim" OR "trimesan" OR "trimethoprin" OR "trimetoprim" OR "trimfect" OR "trimono" OR "trimopan" OR "trinopan" OR "triprim" OR "trisul" OR "uretrim" OR "utisept" OR "welcoprim" OR "wellcoprim" OR

"Cephalosporin*" OR "cefalosporin*" OR

"Cefuroxim*" OR "Cephuroxim*" OR "Zinacef" OR "Ketocef" OR "aksef" OR "alporin" OR "altacef" OR "anaptivan" OR "aprok" OR "aprokam" OR "biocefal" OR "cefoxurime" OR "cefumax" OR "ceplus" OR "ceroxime" OR "curocef" OR "curoxim" OR "curoxima" OR "curoxime" OR "eroxmit" OR "froxal" OR "fucerox" OR "furoxime" OR "iceca" OR "intracef" OR "kefazol" OR "kefurim" OR "kefurox" OR "kesint" OR "laxinat" OR "maxil" OR "normafenac" OR "polixima" OR "prokam" OR "supacef" OR "tarsime" OR "ucefaxim" OR "ultroxim" OR "uroxime" OR "vekfazolin" OR "ximaract" OR "zinocef")

WoS Core Collection 11122023 => 1 + 2 = 1237 results

1. Bronchiectasis

TS=("bronchiectas*"OR "bronchoectasia")

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2. Long term oral antibiotic treatment (excluding long-term macrolides)

TS=("anti-bacterial" OR "antibacterial" OR "Bacteriocid*" OR "anti-mycobacterial" OR "antimycobacterial" OR "antibiotic*" OR

"fluoroquinolon*" OR "quinolon*" OR "chinolon*" OR "quinolin*" OR "chinolin*" OR

"cipro*" OR "ciprinol" OR "aceoto" OR "acire" OR "alcon cilox" OR "apulmiq" OR "araxacina" OR "aristin-c" OR "auripro" OR "bacquinor" OR "bactiflox" OR "baflox" OR "basemar" OR "battizer" OR "baycip" OR "bernoflox" OR "bivorilan" OR "bosix" OR "c-flox" OR "c-floxacin" OR "catex" OR "cetraflux" OR "cetraxal" OR "chinocid" OR "cidroxal" OR "cifin" OR "ciflan" OR "ciflo" OR "ciflosin" OR "ciflot" OR "ciflox" OR "cifloxin" OR "cifox" OR "cifran" OR "cilab" OR "ciloquin" OR "ciloxan" OR "ciloxin" OR "cimogal" OR "cinaflox" OR "cipad" OR "ciperus" OR "cipflox" OR "ciphin" OR "cipide" OR "cipio" OR "ciplox" OR "ciplus" OR "cipocin" OR "ciprecu" OR "ciriax" OR "cirok" OR "cirokan" OR "cirox" OR "ciroxin" OR "citopcin" OR "citrovenot" OR "cobay" OR "corsacin" OR "cosflox" OR "cuminol" OR "cuspis" OR "cycin" OR "cyfloxin" OR "cypral" OR "cyprobay" OR "cysfec" OR "doriman" OR "droll" OR "eoxin" OR "eprocin" OR "estecina" OR "felixene" OR "fimoflox" OR "flociprin" OR "flontalexin" OR "floroxin" OR "floxager" OR "floxantina" OR "floxbio" OR "fonterra" OR "generflon" OR "gerbat" OR "ginorectol" OR "giroflox" OR "gonning" OR "grifociprox" OR "h-next" OR "holdestin" OR "ibixacin" OR "inciflox" OR "infectocipro" OR "inkamil" OR "iprolan" OR "isotic" OR "jayacin" OR "k-sacin" OR "kenzoflex" OR "kinoves" OR "kinox" OR "kipocin" OR "labentrol" OR "ladinin" OR "limox" OR "linhaliq" OR "lipoquin" OR "lofucin" OR "loxan" OR "macar" OR "medociprin" OR "mitroken" OR "nafloxin" OR "neofloxin" OR "nivoflox" OR "novidat" OR "novoquin" OR "oftacilox" OR "opthaflox" OR "otanol" OR "otiprio" OR "otociprin" OR "otosec" OR "phaproxin" OR "pharcina" OR "poncoflox" OR "probiox" OR "prociflor" OR "procin" OR "proflaxin" OR "profloxin" OR "proksi 250" OR "proksi 500" OR "proquin" OR "proxacin" OR "pulmaquin" OR "qilaflox" OR "qinosyn" OR "quilox" OR "quinobiotic" OR "quinoflox" OR "quinolide" OR "quinox" OR "quintor" OR "qupron" OR "rancif" OR "ravalton" OR "revionorm" OR "rigoran" OR "rofcin" OR "roflazin" OR "rosacin eye drop" OR "samper" OR "sarf" OR "sepcen" OR "septicide" OR "septocipro" OR "sifloks" OR "siprogut" OR "siprox" OR "sophixin ofteno" OR "spitacin" OR "strox" OR "suiflox" OR "superocin" OR "syntoflox" OR "topistin" OR "truoxin" OR "ufexil" OR "ullax" OR "unex" OR "unicexal" OR "uniflox" OR "urodixin" OR "uroxin" OR "viprolox" OR "zindolin" OR "zipra" OR "zumaflox" OR

"Levofloxacin*" OR ("(S)-isomer" NEAR/3 "Ofloxacin") OR "Quixin" OR "Levaquin" OR "aeroquin" OR "cravit" OR "elequine" OR "eyflox" OR "floxacin" OR "floxel" OR "iquix" OR "leroxacin" OR "lesacin" OR "levokacin" OR "levox" OR "levoxacin" OR "mosardal" OR "nofaxin" OR "oftaquix" OR "oxalux" OR "prixar" OR "quinsair" OR "reskuin" OR "supraflox" OR "tavanic" OR "unibiotic" OR "venaxan" OR "volequin" OR

"ofloxacin*" OR "tarivid" OR "akilen" OR "audret" OR "bactocin" OR "bioquil" OR "danoflox" OR "effexin" OR "eukinoft" OR "exocin" OR "exocine" OR "flobacin" OR "flodemex" OR "flotavid" OR "flovid" OR "floxal" OR "floxedol" OR "floxigen" OR "floxil" OR "floxin" OR "floxstat" OR "fugacin" OR "grenis-oflo" OR "gyroflox" OR "inoflox" OR "kinflocin" OR "kinoxacin" OR "liflox" OR "loxinter" OR "marfloxacin" OR "medofloxin" OR "medofloxine" OR "mergexin" OR "monoflocet" OR "monoox" OR "novecin" OR "nufafloqo" OR "o-flox" OR "obide" OR "occidal" OR "ocuflox" OR "ofcin" OR "oflin" OR "oflocee" OR "oflocet" OR "oflocin" OR "oflodal" OR "oflodex" OR "oflodinex" OR "oflodura" OR "oflogen" OR

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"oflohexal" OR "oflovir" OR "oflox" OR "ofloxa-vision" OR "ofloxacino" OR "ofloxamed" OR "ofloxavis" OR "ofloxin" OR "ofus" OR "onexacin" OR "operan" OR "orocin" OR "otiflox" OR "otonil" OR "ottoflox" OR "oxacid" OR "oxatrex" OR "pharflox" OR "praxin" OR "puiritol" OR "qinolon" OR "qipro" OR "quinofree" OR "quinolon" OR "quotavil" OR "rilox" OR "romacin" OR "sinflo" OR "surnox" OR "tabrin" OR "taravid" OR "tariflox" OR "taroflox" OR "telbit" OR "trafloxal" OR "tructum" OR "urotarivid" OR "viotisone" OR "visuab" OR "zanocin" OR

"Moxifloxacin*" OR "Octegra" OR "Proflox" OR "Avelox" OR "Avalox" OR "Izilox" OR "Actira" OR "avelon" OR "bacterol" OR "floxamic" OR "floxitrat" OR "izilox" OR "kanavig" OR "lifodrox" OR "megaxin" OR "melocin" OR "moksacin" OR "monafox" OR "moxeza" OR "moxibay" OR "moxif" OR "moxivig" OR "octegra" OR "proflox" OR "tamvelier" OR "vamocin" OR "vegamox" OR "vigamox" OR "vigamoxi" OR "xiflodrop" OR "zimoxin" OR

"penicillin*" OR

"Amoxicillin*" OR "Amoxycillin*" OR "Hydroxyampicillin" OR "Actimoxi" OR "Clamoxyl" OR "Penamox" OR "Polymox" OR "Trimox" OR "Wymox" OR "Amoxil" OR "a gram" OR "abdimox" OR "acilina" OR "acimox" OR "adbiotin" OR "agerpen" OR "agram" OR "alfamox" OR "alfoxil" OR "almodan" OR "almorsan" OR "alphamox" OR "amagesen solutab" OR "ameclina" OR "amitron" OR "amo-flamisan" OR "amo-flamsian" OR "amocillin" OR "amoclen" OR "amodex" OR "amoflux" OR "amohexal" OR "amolin" OR "amonex" OR "amopen" OR "amophar ge" OR "amosine" OR "amoval" OR "amoxa" OR "amoxal" OR "amoxapen" OR "amoxaren" OR "amoxcil" OR "amoxcillin" OR "amoxcin" OR "amoxi-basan" OR "amoxicilina" OR "amoxiclin" OR "amoxicot" OR "amoxidal" OR "amoxidin" OR "amoxidrops" OR "amoxihexal" OR "amoxillin" OR "amoxina" OR "amoxipen" OR "amoxipenil" OR "amoxisol" OR "amoxivan" OR "amoxivet" OR "amoxy" OR "amoxy-diolan" OR "amoxypen" OR "ampliron" OR "apo-amoxi" OR "ardine" OR "aroxin" OR "azillin" OR "bacihexal" OR "bactamox" OR "bactox ge" OR "beamoxy" OR "betamox" OR "bimox" OR "bintamox" OR "biomox" OR "biotamoxal" OR "bioxidona" OR "bioxyllin" OR "bristamox" OR "broadmetz" OR "cabermox" OR "cilamox" OR "clamox" OR "clearamox" OR "clonamox" OR "coamoxin" OR "damoxicil" OR "dispermox" OR "doxamil" OR "draximox" OR "edamox" OR "efpinex" OR "erphamoxy" OR "eupen" OR "farconcil" OR "fisamox" OR "flemoxin" OR "flemoxine ge" OR "fluamoxina" OR "foxolin" OR "fullcilina" OR "gexcil" OR "gimalxina" OR "glamox" OR "glassatan" OR "gomcillin" OR "grinsul" OR "grunamox" OR "hamoxillin" OR "hiconcil" OR "hidramox" OR "hipen" OR "hosboral" OR "ibamox" OR "ibiamox" OR "ikamoxil" OR "imacillin" OR "imaxilin" OR "inamox" OR "infectomycin" OR "intermox" OR "isimoxin" OR "izoltil" OR "julphamox" OR "jutamox" OR "kamoxin" OR "ladoxillin" OR "lamoxy" OR "larocilin" OR "larocin" OR "larotid" OR "macromox" OR "magnimox" OR "maxamox" OR "maxcil" OR "medimox" OR "meixil" OR "metifarma" OR "mopen" OR "morgenxil" OR "moxacin" OR "moxaline" OR "moxarin" OR "moxatag" OR "moxilen" OR "moxilin" OR "moximar" OR "moxitab" OR "moxtid" OR "moxylin" OR "moxypen" OR "moxyvit" OR "neogram" OR "novabritine" OR "novamox" OR "novamoxin" OR "novenzymin" OR "novoxil" OR "nuvosyl" OR "optium" OR "oramox" OR "ospamox" OR "pamocil" OR "pamoxicillin" OR "pamoxin" OR "panvilon" OR "pasetocin" OR "penbiosyn" OR "pentyloxycillin" OR "pharmoxyl" OR "piramox" OR "pondnoxcill" OR "rancil" OR "ranmoxy" OR "ranoxil" OR "ranoxyl" OR "robamox" OR "romoxil" OR "ronemox" OR "saltermox" OR "sawacillin" OR "sawamezin" OR "servamox" OR "shamoxil" OR "sia-mox" OR "sigamopen" OR "sil-a-mox" OR "silamox" OR "simoxil" OR "sintopen" OR "solamocta" OR "solpenox" OR "sumox" OR "superpeni" OR "teramoxyl" OR "tolodina" OR "tormoxin" OR "triafamox" OR "triamoxil" OR "trifamox" OR "uro clamoxyl" OR "uroclamoxyl" OR "utimox" OR "vastamox" OR "velamox" OR "vistrep" OR "widecillin" OR "winpen" OR "xiltrop" OR "zamocillin" OR "zamox" OR "zamoxil" OR "zerrsox" OR "zimox" OR

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"Co-amoxiclav" OR "Coamoxiclav" OR "Amoxi-Clavulanate" OR "Amox-clav" OR "Synulox" OR "Spektramox" OR "Augmentin" OR "Clavulin" OR "aclam" OR "aktil" OR "ambilan" OR "amocla" OR "amoclan" OR "amoclane" OR "amoclav" OR "amoksiklav" OR "amolanic" OR "amometin" OR "amoxi plus" OR "amoxiclav" OR "amoxiclav-bid" OR "amoxiclav-teva" OR "amoxsiklav" OR "amoxxlin" OR "ancla" OR "auclatin duo dry syrup" OR "augamox" OR "augmaxcil" OR "augmentan" OR "augmentine" OR "augmex" OR "augpen" OR "augucillin duo" OR "augurcin" OR "ausclav" OR "auspilic" OR "bactiv" OR "bactoclav" OR "bioclavid" OR "cavumox" OR "ciblor" OR "clacillin duo dry syrup" OR "clamax" OR "clamentin" OR "clamobit" OR "clamonex" OR "clamovid" OR "clamoxin" OR "clamoxyl duo 400" OR "clamoxyl duoforte" OR "clarin-duo" OR "clavam" OR "clavamox" OR "clavar" OR "clavinex" OR "clavodar" OR "clavoxil" OR "clavoxilin plus" OR "clavubactin" OR "clavucid" OR "clavudale" OR "clavulox duo" OR "clavumox" OR "co amoxyclav" OR "coamoxyclav" OR "cramon duo" OR "croanan duo dry syrup" OR "curam" OR "danoclav" OR "darzitil plus" OR "duamentin" OR "duomox" OR "e-moxclav" OR "enhancin" OR "eumetinex" OR "fleming" OR "forcid" OR "forcid solutab" OR "fugentin" OR "fullicilina plus" OR "gumentin" OR "hibiotic" OR "inciclav" OR "klamonex" OR "kmoxilin" OR "lactamox" OR "lansiclav" OR "moxiclav" OR "moxicle" OR "moxyclav" OR "natravox" OR "neoduplamox" OR "noprilam" OR "nufaclav" OR "omep plus" OR "palentin" OR "quali-mentin" OR "ranclav" OR "spectramox" OR "stacillin" OR "strenzen" OR "suplentin" OR "synermox" OR "taromentin" OR "taromentin es" OR "velamox cl" OR "vestaclav" OR "viaclav" OR "vulamox" OR "xiclav" OR "zami 8503" OR

"floxacillin*" OR "Fluorochloroxacillin" OR "Flucloxacillin" OR "flopen" OR "floxapen" OR "flucil" OR "heracillin" OR "stafoxil" OR "staphylex" OR

"Tetracyclin*" OR

"Doxycyclin*" OR "Vibramycin*" OR "Atridox" OR "Doryx" OR "Hydramycin" OR "Oracea" OR "Periostat" OR "Vibra-Tabs" OR "Vibravenos" OR "adoxa" OR "amermycin" OR "apprilon" OR "atrax" OR "azudoxat" OR "bactidox" OR "banndoclin" OR "basedillin" OR "bassado" OR "biocolyn" OR "biodoxi" OR "bronmycin" OR "cloran" OR "cyclidox" OR "dentistar" OR "deoxycycline" OR "deoxymycin dispersal" OR "deoxymykoin" OR "deoxyoxytetracycline" OR "desoxy oxytetracycline" OR "desoxycycline" OR "doinmycin" OR "dosil" OR "dotur" OR "doxaciclin" OR "doxacycline" OR "doxat" OR "doxatet" OR "doxi -sergo" OR "doxibiotic" OR "doxicycline" OR "doxilin" OR "doximed" OR "doximycin" OR "doxin" OR "doxine" OR "doxirobe" OR "doxocycline" OR "doxsig" OR "doxy" OR "doxybiocin" OR "doxycen" OR "doxychel" OR "doxycin" OR "doxylag" OR "doxylin" OR "doxymycin" OR "doxypuren" OR "doxytec" OR "doxytrim" OR "dumoxin" OR "duracycline" OR "efracea" OR "esdoxin" OR "etidoxina" OR "gewacyclin" OR "ibralene" OR "idocyclin" OR "idocyklin" OR "interdoxin" OR "investin" OR "longamycin" OR "lydox" OR "magdrin" OR "medomycin" OR "mespafin" OR "mildox" OR "miraclin" OR "monodox" OR "nanodox" OR "nordox" OR "oraycea" OR "paldomycin" OR "pernox gel" OR "radox" OR "remycin" OR "respidox" OR "roximycin" OR "serodoxy" OR "servidoxine" OR "servidoxyne" OR "siadocin" OR "siclidon" OR "sigadoxin" OR "spanor" OR "supracyclin" OR "supramycina" OR "tenutan" OR "tolexine" OR "torymycin" OR "tsurupioxin" OR "unidox" OR "veemycin" OR "viadoxin" OR "vibra s" OR "vibra-s" OR "vibrabiotic" OR "vibracina" OR "vibradox" OR "vibramicina" OR "vibraveineuse" OR "vibravet" OR "viradoxyl-n" OR "wanmycin" OR "xyrosa" OR "zadorin" OR "zenavod" OR

"Minocyclin*" OR "Minox 50" OR "Aknemin" OR "Aknin-Mino" OR "Aknosan" OR "Mynocine" OR "Arestin" OR "Blemix" OR "Cyclomin" OR "Cyclops" OR "Dentomycin" OR "Dynacin" OR "Icht-Oral" OR "Klinomycin" OR "Lederderm" OR "Mestacine" OR "Minakne" OR "Mino on September 29, 2025 by guest. Please see licensing information on first page for reuse rights.

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Wolff" OR "Minocin" OR "Minoclir" OR "Minolis" OR "Minomycin" OR "Minoplus" OR "Minotab" OR "Akamin" OR "Akne-Puren" OR "amzeeq" OR "borymycin" OR "cipancin" OR "cyclimycin" OR "cynomycin" OR "klinotab" OR "kyno" OR "logryx" OR "menocycline" OR "micromycin" OR "minaxen" OR "mino-50" OR "minoclin" OR "minocyn" OR "minogalen" OR "minoline" OR "minolira" OR "minomax" OR "minosil" OR "minostad" OR "minotrex" OR "minoz ep" OR "mirosin" OR "parocline" OR "periofeel" OR "romin" OR "sebomir" OR "skinocyclin" OR "solodyn" OR "spicline" OR "vectran" OR "vectrin" OR "ximino" OR "zilxi" OR

"sulfanilamide*" OR "sulfonamide*" OR "sulphanilamide*" OR "sulphonamide*" OR

"Centrin" OR "Cotrimoxazole" OR "Co-Trimoxazole" OR "Eslectin" OR "Insozalin" OR "Trimezol*" OR "Centran" OR "Trimedin" OR "Septrin*" OR "Bactifor" OR "Sumetrolim" OR "Abactrim" OR "Bactrim" OR "Biseptol" OR "Biseptol480" OR "Drylin" OR "Eusaprim" OR "Kepinol" OR "Lescot" OR "Metomide" OR "Oriprim" OR "Septra" OR "Sulprim" OR "Trimosulfa" OR "abactrin" OR "alfatrim" OR "apo sulfatrim" OR "bactar" OR "bactipront" OR "bactoreduct forte" OR "bactramin" OR "bactrimel" OR "bethaprim" OR "bispetol" OR "chemotrim" OR "comox" OR "comoxol" OR "cotrim" OR "cotrimoxazol forte" OR "cotrimstada forte" OR "deprim" OR "deprim forte" OR "duobact" OR "duobiocin" OR "duobiocin forte" OR "duratrimet" OR "eltrianyl" OR "escoprim" OR "espectrin" OR "fectrim" OR "groprim" OR "helveprim" OR "imexim" OR "infectrim" OR "lagaprim" OR "lagatrim" OR "linaris" OR "microtrim" OR "neoprim" OR "nopil" OR "oecotrim" OR "omsat" OR "oribact" OR "pharmaprim" OR "potesept" OR "resprim" OR "resprin" OR "scanprin" OR "septran" OR "septrim" OR "sigaprim" OR "sinersol" OR "soltrim" OR "sulfamethoprim" OR "sulfaprim" OR "sulfatrim" OR "sulfotrim" OR "sulmeprim" OR "sumetrolin" OR "supracombin" OR "thiocuran" OR "tms forte" OR "trib" OR "trigonyl" OR "trimeth/sulfa" OR "trimetoprim-sulfa" OR "trimetoprimsulfamethoxazole" OR "trimforte" OR "trimoxazole" OR "trimoxol" OR "uro ts d" OR "uroplus ds" OR "uroplus ss" OR

"pyrimidin*" OR

"trimethoprim*" OR "trimpex" OR "proloprim" OR "abaprim" OR "alprim" OR "catin" OR "delprim" OR "giprim" OR "idotrim" OR "infectotrimet" OR "methoprim" OR "monoprim" OR "monotrim" OR "motrim" OR "primosept" OR "primsol" OR "solotrim" OR "syraprim" OR "tiempe" OR "tmp-ratiopharm" OR "tobyprim" OR "trimesan" OR "trimethoprin" OR "trimetoprim" OR "trimfect" OR "trimono" OR "trimopan" OR "trinopan" OR "triprim" OR "trisul" OR "uretrim" OR "utisept" OR "welcoprim" OR "wellcoprim" OR

"Cephalosporin*" OR "cefalosporin*" OR

"Cefuroxim*" OR "Cephuroxim*" OR "Zinacef" OR "Ketocef" OR "aksef" OR "alporin" OR "altacef" OR "anaptivan" OR "aprok" OR "aprokam" OR "biocefal" OR "cefoxurime" OR "cefumax" OR "ceplus" OR "ceroxime" OR "curocef" OR "curoxim" OR "curoxima" OR "curoxime" OR "eroxmit" OR "froxal" OR "fucerox" OR "furoxime" OR "iceca" OR "intracef" OR "kefazol" OR "kefurim" OR "kefurox" OR "kesint" OR "laxinat" OR "maxil" OR "normafenac" OR "polixima" OR "prokam" OR "supacef" OR "tarsime" OR "ucefaxim" OR "ultroxim" OR "uroxime" OR "vekfazolin" OR "ximaract" OR "zinocef" )

NOT DT=("meeting abstract")

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PICO 6

Pubmed (including Medline) 11122023 => 1 + 2 = 924 results

3. Bronchiectasis

"Bronchiectasis"[Mesh] OR "bronchiectas*"[tiab] OR "bronchoectasia"[tiab]

4. Eradication

Eradicat*[tiab] OR clearance[tiab] OR eliminat*[tiab]

Embase 11122023 => 1 + 2 = 1372 results

5. Bronchiectasis

'bronchiectasis'/exp OR 'bronchiectas*':ti,ab,kw OR 'bronchoectasia':ti,ab,kw

6. Eradication

'pathogen clearance'/exp OR 'eradication therapy'/exp OR Eradicat*:ti,ab,kw OR clearance:ti,ab,kw OR eliminat*:ti,ab,kw

NOT 'conference abstract'/it

Scopus 11122023 => 1 + 2 = 1243 results

1. Bronchiectasis

TITLE-ABS("bronchiectas*"OR "bronchoectasia") OR AUTHKEY("bronchiectas*"OR "bronchoectasia")

2. Eradication

TITLE-ABS(Eradicat* OR clearance OR eliminat*) OR AUTHKEY(Eradicat* OR clearance OR eliminat*)

WoS 11122023 => 1 + 2 = 837 results

1. Bronchiectasis

TS=("bronchiectas*" OR "bronchoectasia")

2. Eradication

TS=(Eradicat* OR "clearance" OR eliminat*)

NOT DT=("meeting abstract")

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Narrative 1

Pubmed (including Medline) 24012024 => 2716 results

3. Bronchiectasis

"Bronchiectasis"[Mesh] OR "bronchiectas*"[tiab] OR "bronchoectasia"[tiab]

4. Etiology/Severity/comorbidity/…

"Bronchiectasis/etiology"[Mesh:NoExp] OR "Patient Acuity"[Mesh] OR "Comorbidity"[Mesh] OR "caus*"[tiab] OR "etiolog*"[tiab] OR "aetiolog*"[tiab] OR "severity"[tiab] OR "comorbid*"[tiab] OR "co-morbid*"[tiab] OR "multimorbid*"[tiab] OR multi-morbid*[tiab] OR "concurrent chronic"[tiab] OR "multipe chronic"[tiab:~0] OR "simultaneous chronic"[tiab] OR "long term condition*"[tiab] OR "longterm condition*"[tiab] OR "coexist*"[tiab] OR "coexist*"[tiab] OR "Cumulative Illness Rating Scale"[tiab] OR "treatable trait*"[tiab]

((1) AND (2))

AND 2014/01/01:3000/12/31[crdt]

Narrative 1 (checked and approved)

PMID

11029331[uid] OR 26431397[uid] OR 27864036[uid]

Embase (Embase.com) 24012024 => 4075 results

5. Bronchiectasis

'bronchiectasis'/exp OR 'bronchiectas*':ti,ab,kw OR 'bronchoectasia':ti,ab,kw

6. Etiology/Severity/comorbidity/…

'bronchiectasis'/exp/dm_et OR 'disease severity assessment'/exp OR 'disease severity'/de OR 'comorbidity'/exp OR 'comorbidity assessment'/exp OR 'comorbidity index'/exp OR 'multiple chronic conditions'/exp OR 'etiolog*':ti,ab,kw OR 'aetiolog*':ti,ab,kw OR 'severity':ti,ab,kw OR 'comorbid*':ti,ab,kw OR 'co-morbid*':ti,ab,kw OR 'multimorbid*':ti,ab,kw OR 'multi-morbid*':ti,ab,kw OR 'concurrent chronic':ti,ab,kw OR 'multipe chronic':ti,ab,kw OR 'simultaneous chronic':ti,ab,kw OR 'long term condition*':ti,ab,kw OR 'longterm condition*':ti,ab,kw OR 'coexist*':ti,ab,kw OR 'co-exist*':ti,ab,kw OR 'Cumulative Illness Rating Scale':ti,ab,kw OR (('bronchiectas*' OR 'bronchoectasia') NEAR/9 ('caus*')):ti,ab,kw OR 'treatable trait'/exp OR 'treatable trait*':ti,ab,kw

(((1) AND (2))

NOT 'conference abstract':it)

AND [01-01-2014]/sd NOT [01-01-3001]/sd

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Scopus 11122023 => 2585 results

1. Bronchiectasis

TITLE-ABS("bronchiectas*"OR "bronchoectasia") OR AUTHKEY("bronchiectas*"OR "bronchoectasia")

2. Exacerbation

TITLE-ABS("caus*" OR "etiolog*" OR "aetiolog*" OR "severity" OR "comorbid*" OR "comorbid*" OR "multimorbid*" OR "multi-morbid*" OR "concurrent chronic" OR "multipe chronic" OR "simultaneous chronic" OR "Cumulative Illness Rating Scale" OR "long term condition*" OR "longterm condition*" OR "coexist*" OR "co-exist*" OR "treatable trait*") OR AUTHKEY("caus*" OR "etiolog*" OR "aetiolog*" OR "severity" OR "comorbid*" OR "comorbid*" OR "multimorbid*" OR "multi-morbid*" OR "concurrent chronic" OR "multipe chronic" OR "simultaneous chronic" OR "Cumulative Illness Rating Scale" OR "long term condition*" OR "longterm condition*" OR "coexist*" OR "co-exist*" OR "treatable trait*")

((1) AND (2))

AND PUBYEAR > 2013

WoS Core Collection 24012024 => 2335 results

Science Citation Index Expanded

(SCI-EXPANDED)--1955-present

Social Sciences Citation Index

(SSCI)--1956-present

Arts & Humanities Citation Index

(AHCI)--1975-present

Conference Proceedings Citation Index – Science

(CPCI-S)--1990-present

Conference Proceedings Citation Index – Social Science & Humanities (CPCI-SSH)--1990-present

Emerging Sources Citation Index

(ESCI)--2019-present

1. Bronchiectasis

TS=("bronchiectas*"OR "bronchoectasia")

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2. Etiology/Severity/comorbidity/…

TS=("caus*" OR "etiolog*" OR "aetiolog*" OR "severity" OR "comorbid*" OR "co-morbid*" OR "multimorbid*" OR "multi-morbid*" OR "concurrent chronic" OR "multipe chronic" OR

"simultaneous chronic" OR "long term condition*" OR "longterm condition*" OR "coexist*"

OR "co-exist*" OR "Cumulative Illness Rating Scale" OR "treatable trait*")

(((1) AND (2))

NOT DT=("meeting abstract"))

AND LD=2014-01-01/2024-12-31

Narrative 2 and Narrative 3

Pubmed (including Medline) 24012024 => 1 + 2 + 3 = 294 results

3. Bronchiectasis

"Bronchiectasis"[Mesh] OR "bronchiectas*"[tiab] OR "bronchoectasia"[tiab]

4. Exacerbation

"Disease Progression"[Mesh:NoExp] OR "Clinical Deterioration"[Mesh] OR "progressi*"[tiab] OR "exacerbat*"[tiab] OR "deteriorat*"[tiab] OR aggravat*[tiab]

5. Guideline

"Guideline" [Publication Type] OR guideline*[tiab] OR "Guidelines as Topic"[Mesh] OR "Consensus"[Mesh] OR consensus*[tiab] OR "Consensus Development Conferences as Topic"[Mesh] OR "Consensus Development Conference" [Publication Type] OR statement*[tiab] OR "Delphi Technique"[Mesh] OR "delphi"[tiab] OR recommend*[tiab]

Narrative 3 (checked and approved)

PMID

35690367[uid] OR 34261186[uid] OR 32002044[uid] OR 28990652[uid]

Narrative 2 (checked and approved)

PMID

34112732[uid]

Embase (Embase.com) 24012024 => 1 + 2 + 3 = 605 results

6. Bronchiectasis

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'bronchiectasis'/exp OR 'bronchiectas*':ti,ab,kw OR 'bronchoectasia':ti,ab,kw

7. Exacerbation

'disease exacerbation'/de OR 'deterioration'/exp OR 'progressi*':ti,ab,kw OR 'exacerbat*':ti,ab,kw OR 'deteriorat*':ti,ab,kw OR 'aggravat*':ti,ab,kw

8. Guideline

'practice guideline'/de OR guideline*:ti,ab,kw OR 'consensus'/de OR 'consensus development'/exp OR consensus*:ti,ab,kw OR statement*:ti,ab,kw OR 'Delphi study'/exp OR delphi:ti,ab,kw OR 'recommendations'/exp OR 'recommend*':ti,ab,kw

NOT 'conference abstract':it

Scopus 24012024 => 1 + 2 + 3 = 313 results

1. Bronchiectasis

TITLE-ABS("bronchiectas*"OR "bronchoectasia") OR AUTHKEY("bronchiectas*"OR "bronchoectasia")

2. Exacerbation

TITLE-ABS("progressi*" OR "exacerbat*" OR "deteriorat*" OR "aggravat*") OR AUTHKEY("progressi*" OR "exacerbat*" OR "deteriorat*" OR "aggravat*")

3. Guideline

TITLE-ABS("guideline*" OR "consensus*" OR "statement*" OR "delphi" OR "recommend*") OR AUTHKEY("guideline*" OR "consensus*" OR "statement*" OR "delphi" OR "recommend*")

WoS Core Collection 24012024 => 1 + 2 + 3 = 356 results

1. Bronchiectasis

TS=("bronchiectas*"OR "bronchoectasia")

2. Exacerbation

TS=("progressi*" OR "exacerbat*" OR "deteriorat*" OR "aggravat*")

3. Guideline

TS=("guideline*" OR "consensus*" OR "statement*" OR "delphi" OR "recommend*") NOT DT=("meeting abstract")

Embase (Embase.com) 21022025 => ((1 AND 2 AND 3) NOT 'conference abstract':it) AND [24-12-2023]/sd NOT [21-02-2025]/sd = 92 results

1. Bronchiectasis

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'bronchiectasis'/exp OR 'bronchiectas*':ti,ab,kw OR 'bronchoectasia':ti,ab,kw

2. Exacerbation

'disease exacerbation'/de OR 'deterioration'/exp OR 'progressi*':ti,ab,kw OR 'exacerbat*':ti,ab,kw OR 'deteriorat*':ti,ab,kw OR 'aggravat*':ti,ab,kw

3. Guideline

'practice guideline'/de OR guideline*:ti,ab,kw OR 'consensus'/de OR 'consensus development'/exp OR consensus*:ti,ab,kw OR statement*:ti,ab,kw OR 'Delphi study'/exp OR delphi:ti,ab,kw OR 'recommendations'/exp OR 'recommend*':ti,ab,kw

NOT 'conference abstract':it

Appendix 1- evidence summaries and evidence-to-decision frameworks for all questions

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European Respiratory Journal

Page 94 of 177

|European Respiratory Journal Note 94 of 177|Certainty assessment|Certainty|Certainty|Importance|||||||||||||| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---| |European Respiratory Journal Note 94 of 177|Certainty assessment|Certainty|Certainty|Importance|Ne of studies|Study design|Risk of bias|Inconsistency|Indirectness|Imprecision|Other considerations||||||| |2|randomised trials|serious|not serious|not serious|Serious|none|39|40|Not applicable|Median 6.2 higher (0.46 higher to 11.95 higher)||CRITICAL|CRITICAL||||| |Hospitalization at $$\begin{array}{l}\\ \end{array}$$|||||||||||||||||| |Patient satisfaction and feedback|-|-|CRITICAL||||||||||||||| |||||||||No studies were identified for this outcome|||-|CRITICAL|||||| |||||||||No studies were identified for this outcome|||-|CRITICAL|||||| |Cl: confidence interval; MD: mean difference; OR: odds ratio|||||||||||||||||| |Explanations|Explanations|Explanations|Explanations|Explanations|Explanations|Explanations|Explanations|Explanations|Explanations|Explanations|Explanations|Explanations|Explanations||||| ||a. All included studies except Munoz et al are not blinded. 211001111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111|||||||||||||||||

Page 95 of 177

European Respiratory Journal

Author(s): James D Chalmers, Beatriz Herrero, Stefano Aliberti

Question: Should Mucoactive drugs versus No mucoactive drugs be used for bronchiectasis

Setting: Outpatients with bronchiectasis

Bibliography:

1.Bilton D,Tino G,Barker AF,Chambers DC,De Soyza A,Dupont LJ,O'Dochartaich C,van Haren EH, Vidal LO,Weel T,Fox HG,Wu J,Charlton B;B-305 Study Investigators Inhaled mannitol for non-cystic fibrosis bronchiefasis: a randomised, controlled trial.:Thorax.2014 Dec;69(12):1073-9. doi:10.1136/thoraznl-2014-205587.Epub 2014 Sep 21.

2.Bilton D,Daviskas E,Anderson SD,Kolbe J,King G,Stirling RG,Thompson BR,Milne D,Charlton B;B301 Investigators. Phase 3 randomized study of the efficacy and safety of inhaled dry powder mannitol for the symptomatic treatment of non-cystic fibrosis bronchiectasis. Chest.2013 Jul;144(1):215-225

3.Crisafulth,Ecolli O,Costi S,Zanasi E,Lorenzi C,Culic S,Fabbri LM,BertinM.Effectiveness in erdosester in elderly patients with bronchiectasis and hypersecretion: a 15-day, prospective, parallel, open-label, pilot study.CliniEM.Clin Ther.2007 Sep;29(9):2001-9

4.O'Donnell AE,Barker AF,Ilowite JS,Fick RB.Treatment of idiophac biectasis with aerosol recombinant human DNase I,rhDNase Study Group.Chest.1998 May;113(5):1329-34

5.Kellett,F.Robert NM.Nebulised 7% hypertonic saline improves lung function and quality of life in bronchieostasis.Respir Med.2011Dec;105(12):1831-5.

6.Nicolson CH, Stirling RG, Borg BM, Button BM, Wilson JW, Holland AE. The long term effect of inhaled hypertension saline: Respir Med. 2012 May;106(5):661-7

7.Paff T,Daniels JM,Weersink EJ,Lutter R,Yonk Noordegraf A,Haarman E.G.A randomised controlled trial on the effect of inhaled hypertonic saline on quality of life in primary ciliary dyskinesia.Eur Respir J.2017 Feb 23;49(2):1601770

8.Qi Q,Ailyera Y,Liu R,Zhang Y,Li C,Liu M,Wang X,Jing L,Li Y.Effect of N-acetylcysteine on exacerbations of bronchiectasis(BENE): a randomized controlled trial..Respir Res.2019.

9.Wills PJ,Wodehouse T,Corkery K,Mallon K,Wilson R,Cole PJ.Short-term recombinant human DNase in bronchiectasis.Effect on clinical state and in vitro sputum transportability.Am J Respir Crit Care Med.1996

Aug:154(2 Pt 1):413

||Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|No of patients|No of patients|Effect|Effect|Effect|Certainty| |---|---|---|---|---|---|---|---|---|---|---|---|---|---| |Ne of studies|Study design|Risk of bias|Inconsistency|Indirectness|Imprecision|Other considerations|Mucoactive drugs|No mucoactive drugs|Relative (95% CI)|Absolute|||Certainty|

Exacerbations-Exerabation frequency(mean number of exacerbations)1.8

|3|randomised trials|serious|not serious|serious|not serious|non serious|none|334|328|NA|MD 0.28 lower (0.63 lower to 0.07 higher)|$$\oplus\oplus\bigcirc\bigcirc$$ Low ${}^{b}$|CRITICAL| |---|---|---|---|---|---|---|---|---|---|---|---|---|---| |4|||||||||||||| |5|Exacerbations (y<14)|not serious|not serious|non serious|non serious||none|NA/409|NA/401|Rate ratio 0.99 (0.80 to 1.23)|Not estimable|BOOHO Moderate|CRITICAL|

Exacerbations frequency- RR+1

|2|randomised trials|not serious|not serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|

Exacerbations (% participants free of exacerbations during follow-up)+1,2,8

|3|randomised trials|serious ${}^{a}$|serious${}^{d}$|serious${}^{b}$|serious${}^{c}$|none|298/545(54.7%)|161/420 (38.3%)|OR 1.48 (0.88 to 2.51)|96 more per 1,000 (from 30 fewer to 226 more)|$\bigcirc\bigcirc\bigcirc$ $$\text{Very low}^{a,b,c}$$|CRITICAL| |---|---|---|---|---|---|---|---|---|---|---|---|---|

Hospitalisations-(% participants free of hospital admission) ${}^{6}$

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||lambel|lambel|lambel|lambel|lambel|lambel|lambel|lambel|lambel|lambel| |---|---|---|---|---|---|---|---|---|---|---| |PPPOPOPOPO|ABV|ABV|88.1|88.1|88.1|88.1|88.1|88.1|88.1|88.1|

Ambingues and FREY

|TUVLOR|TUVOPO|TUVOPO|TUVOPO|TUVOPO|TUVOPO|TUVOPO|TUVOPO|TUVOPO|TUVOPO|TUVOPO|TUVOPO|TUVOPO|TUVOPO|TUVOPO| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---| |TUVLOR|TUVOPO|TUVOPO|TUVOPO|TUVOPO|TUVOPO|TUVOPO|TUVOPO|TUVOPO|TUVOPO|TUVOPO|TUVOPO|TUVOPO|TUVOPO|TUVOPO|

which will then be used to extract the correct values.

||||||||||| |---|---|---|---|---|---|---|---|---|---| ||||||||||| |||||||||||

(1991, 1992)

|TVALLIO|lope a VMBL|omega VMBL|(Jalouz y 0)|0|SSC|18|8|ws|ws|ws|ws| |---|---|---|---|---|---|---|---|---|---|---|---| |TVALLIO|o|umpeo 0)|YN|SSC|18|8|ws|ws|ws|ws|ws|

(2018)

||age|age|age|age|age|age|page|page|page| |---|---|---|---|---|---|---|---|---|---| |TOLLO|O|O|O|O|E|E|O|O|O|

Sinsuedo s an d -s uasuac s an d uasuad

|TCL|OCL||||||||||||| |---|---|---|---|---|---|---|---|---|---|---|---|---|---| |TCL|OCL|olipelaealipel|olipelaealipel|olipelaealipel|olipelaealipel|olipelaealipel|olipelaealipel|olipelaealipel|olipelaealipel|olipelaealipel|olipelaeal|olipelaealipel|olipelaealipel|

A1 to the left and right the left and right the right

|TOLLII|LOLLII|LOLLII|LOLLII|LOLLII|LOLLII|LOLLII|LOLLII|LOLLII|LOLLII|LOLL|LOLL|LOLL|LOLL|LOLL|LOLL|LOLL|LOLL|LOLL|LOLL|LOLL|LOLL|LOLL|LOLL|LOLL|LOLL|LOLL| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---| |TOLLII|LOLLII|LOLLII|LOLLII|LOLLII|LOLLII|LOLLII|LOLLII|LOLLII|LOLLII|LOLL|LOLL|LOLL|LOLL|LOLL|LOLL|LOLL|LOLL|LOLL|LOLL|LOLL|LOLL|LOLL|LOLL|LOLL|LOLL|LOLL| |Other of the|Other of the||||||||||||||||||||||||||

Page 97 of 177

European Respiratory Journal

|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|No of patients|No of patients|Effect|Effect|Certainty|Importance| |---|---|---|---|---|---|---|---|---|---|---|---|---| |Ne of studies|Study design|Risk of bias|Inconsistency|Indirectness|Imprecision|Other considerations|Mucoactive drugs|No mucoactive drugs|Relative (95% CI)|Absolute (95% CI)|Certainty|Importance|

Patients feedback / continue with treatment

|1|randomised trials|not serious|not serious|serious’s|not serious|none|23/29(79.3%)|6/29(20.7%)|OR 14.69 (4.12 to 52.36)|586 more per 1,000 (from 311 more to 725 more)|$$\oplus\oplus\oplus\circ$$ Moderate|IMPORTANT| |---|---|---|---|---|---|---|---|---|---|---|---|---|

Activities of Daily Living: not reported

|0||||||No data reported for this outcome||||-|| |---|---|---|---|---|---|---|---|---|---|---|---|

CI: confidence interval; HR: hazard ratio; MD: mean difference; OR: odds ratio; SMD: standardised mean difference

Explanations

a.Open label design for Qi et al

b.Control for Nicolson is isotonic saline, Control for mannitol is low dose mannitol.

c.Confidence interval includes relevant benefits and harms

d.Confidence intervals do not fully overlap demonstrating important inconsistency

e.Large amount of data from a subset which is exclusively primary ciliary dyskinesia

f.Cls include benefits without clinical significance (below with minimum clinically important difference)

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European Respiratory Journal

Page 98 of 177

Author(s):James Chalmers and Stefano Alberti

Question: Should Inhaled antibiotics versus No inhaled antibiotics have used for Bronchiaseis

Setting: Outpatients with broncheticasis

Bibliography:

1.$\_$D. Soeya A.,Aksami T.,Bandel,T.-J.Respire 3: a phase III placebo-controlled randomised trial of croxifproloxicody powder for inhalation in non-cystic fibrosis bronchiectasis Eur Respir J.2018;51,1702052

1.Atsam, T.-De Soya, A. Bandel, T.-J...RESPIRE 2: a phase III placebo-controlled randomised trial of ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis Eur Respir J. 2018; 51, 1702052

3.Haworth, C.S., Biton, D., Chalmers, J.D., Inhaled liposarina coptrioxolacin in patients with non-cystic fibrosis bronchiefects and chronic lung infection with Pseudomonas aeruginosa(ORBIT-3 and ORBIT-4): two phase 3, randomised controlled trials Lancet Respir Med.2019;7:213-226

4.Siserier,D.J.Bilton,D.-De Soya,za.A.Inhalos,D.-De Soya,za.A.Inhalos,D.-De Soya,za.A.Inhalos,D.-De Soya,za.A.Inhalos,D.-De Soya,za.A.Inhalos,D.-De Soya,za.A.Inhalos,D.-De Soya,za.A.Inhalos,D.-De Soya,za.A.Inhalos,D.-De Soya,za.A.Inhalos,D.-De Soya,za.A.Inhalos,D.-De Soya,za.A.Inhalos,D.-De Soya,za.A.Inhalos,D.-De Soya,za.A.Inhalos,D.-De Soya,za.A.Inhalos,D.-De Soya,za.A.Inhalos,D.-De Soya,za.A.Inhalos,D.-De Soya,za.A.Inhalos,D.-De Soya,za.A.Inhalos,D.-De Soya,za.A.Inhalos,D.-De Soya,za.A.Inhalo

5.Murray,M.P.G.,Govan,J.R.W.Doherty,C.J.A randomized controlled trial of nebulized gemarcin in non-cystic fibrosis bronchiefectsiamis Am J Respir Crit Care Med.2011;183:491-499

Drobin, M.E., Suéi, P., Montoro, J.B. Inhaled torraminary in non-cystic fibrosis patients with bronchiosis and chronic bronchial infection with Pseudomonas aeruginosa Ann Pharmacother. 2005; 39:44-47.

8.Guan,W.,Xu,J.,Luo,H.A double-blind randomized placebo-controlled placebo-3001 phoscular asin B with bronchictasis at patients with bronchictasis and chronic Pseudomonas aeruginosa infection for B with Pseudomonas aeruginosa infection.

9.Haworth, C.S., Foweraker, J.E., Wilkinson, L.\,Inhalated colombinatic in methyberonchis et al. with bronchieonctasis and chronic Pseudomonas aeruginosa infection on Am J Respir Crit Care Med.2023; 163:64-76

10.Barker,A.F.,O'Donnell,A.E.,Flume,A.P.,Zreatromon in inhalation solution in patients with non-cystic fibrosis bronchiectasis(AIR-BX1 and AIR-BX2); two randomised double-blind, placebo-controlled phase 3 trials Lncent Respir Med. 2014; 2:738-749

11.Oriols,R.-R.,Giort,·F.,Jerrer,J.Inhaled antibiotic therapy in non-cystic fibrosis patients with bronchotic and chronic bronchiefasis: A Blyreson, M. and IR-B11 and AIR-B2): two randomised double-blind, placebo-controlled phase 3 trials Lancet Respir Med. 2014;2:738-749

13. Baker, A.F.,Couch,L.,Lefi, B.,Turbycin DNA, D. Prazonin for inhalation reduction sputum Pseudomonas aeruginosa density in bronchiectasis Am J Respir Crit Care Med. 2000; 162:481-485

14.Terpta,C.L.,Attenburg,J.,Bronsweld,I.Effects of long-term tobramycin inhalation solution(TIS) once daily on excitation rate in patients with non-cystic fibrosis bronchiectasis Respir Res.2022;23:330

15. Hawthorn CS,Shenberg M. Windrop K et al. Inhaled colistrate sodium in patients with bronchocasis and Pseudomonas acid oxygenin infection: results of PROMIS-I and PROMIS-II, two randomised, double-blind, placebo-controlled phase 3 trials assessing safety and efficacy over 12 months. Lancet Respir Med.2024 Sép 6:2231260(2004)0225-X

||Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Certainty|Importance| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---| ||No of studies|Study design|Risk of bias|Inconsistency|Indirectness|Imprecision|Other considerations|Inhal69 of patients|No inhaled antibiotics|Relative (95% CI)|Absolute (95% CI)|Certainty|||Certainty|Importance| |15||||||||||||||||| |26||||||||||||||||| |39||||||||||||||||| |40||||||||||||||||| |50||||||||||||||||| |42||||||||||||||||| |53||||||||||||||||| |44||||||||||||||||| |26||||||||||||||||| |39||||||||||||||||| |44||||||||||||||||| |45||||||||||||||||| |46||||||||||||||||| |47|||||||||||||||||

Frequency of exacerbations 12,3,7,8,10,14,15

|13|randomised trials|not serious|not serious|not serious|not serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious|non-62.20|Non-scales, and other subtasks|non-scales, and other subtasks are non-scales. Non-scales, and other subtasks are non-scales. Non-scales, and other subtasks are non-scales. Non-scales, and other subtasks are non-scales. Non-scales, and other subtasks are non-scales. Non-scales, and other subtasks are non-scales. Non-scales, and other subtasks are non-scales. Non-scales, and other subtasks are non-scales. Non-scales, and other subtasks are non-scales. Non-scales, and other subtasks are non-scales. Non-scales, and other subtasks are non-scales. Non-scales, and other subtasks are non-scales. Non-scales, and other subtasks are non-scales. Non-scales, and other subtasks are non-scales. Non-scales, and other subtasks are non-scales. Non-scales, and other subtasks are non-scales. Non-scales, and other subtasks are non-scales. Non-scales, and other subtasks are non-scales. Non-scales, and ot| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|

Number of patients with at least one exacerbation1,2,3,4,5,7,8,8,10,12,15,14,15

|18|randomised trials|not serious|not serious|not serious|not serious|not serious|non serious|none|830/2108(39.4%)|667/1550(43.0%)|RR 0.85 (0.76 to 0.94)|65 fewer per (from 103 fewer to 26 fewer)|CRITICAL| |---|---|---|---|---|---|---|---|---|---|---|---|---|---| |29|||||||||||||| |30|||||||||||||| |4|||||||||||||| |Frequency of severe exacerbations 3,8,7,11,12,15||||||||||||||

Frequency of severe exacerbations

|8|randomised trials|not serious|not serious|not serious|not serious|non serious|non-700|NA/880|NA/628|Rate ratio 0.57 (0.35 to 0.94)|Not estimable|$\boxplus \boxplus \oplus$ High|CRITICAL| |---|---|---|---|---|---|---|---|---|---|---|---|---|---| |15|||||||||||||| |26|||||||||||||| |39|||||||||||||| |40|||||||||||||| |5|||||||||||||| |42|||||||||||||| |43|||||||||||||| |44|||||||||||||| |45|||||||||||||| |46|||||||||||||| |47||||||||||||||

Time to first exacerbation1,2,3,7,8,8,10,14,15

|14|randomised trials|not serious|not serious|not serious|not serious|non serious|none|NA/1800|NA/1319|HR 0.81 (0.71 to 0.93)|Not estimable|$\boxplus\boxplus\boxplus\oplus$ High|CRITICAL| |---|---|---|---|---|---|---|---|---|---|---|---|---|---| |45||||||||||||||

QOL-B RSS1,2,3,7,8,10,14

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Page 99 of 177

European Respiratory Journal

|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|No of patients|No of patients|Effect|Effect|Certainty|Importance|| |---|---|---|---|---|---|---|---|---|---|---|---|---|---| |Ne of studies|Study design|Risk of bias|Inconsistency|Indirectness|Imprecision|Other considerations|Inhaled antibiotics|No inhaled antibiotics|Relative (95% CI)|Absolute|Certainty|Importance|| |11|randomised trials|not serious|not serious|not serious|non serious||1399|916|NA-|MD 2.14 higher (0.28 lower to 4.57 higher)|$\oplus$ $\oplus$ $\bigcirc$ $\bigcirc$ Moderatea|CRITICAL|| |SGRQ1,4,6,9,12,15|SGRQ1,4,6,9,12,15|SGRQ1,4,6,9,12,15|SGRQ1,4,6,9,12,15|SGRQ1,4,6,9,12,15|SGRQ1,4,6,9,12,15|SGRQ1,4,6,9,12,15|SGRQ1,4,6,9,12,15|SGRQ1,4,6,9,12,15|SGRQ1,4,6,9,12,15|SGRQ1,4,6,9,12,15|SGRQ1,4,6,9,12,15|SGRQ1,4,6,9,12,15|SGRQ1,4,6,9,12,15|

SGRQ1,2,4,6,9,12,15

|8|randomised trials|not serious|not serious|not serious|serious|non serious||non non|1105|774|NA|MD 2.63 lower (5.37 lower to 0.1 higher)|$$\oplus\oplus\oplus\bigcirc$$ Moderatea|CRITICAL| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---| |13|slates with resistant MIC at the end of treatment ${}^{+15}$||||||||||||||

Isolates with resistant MIC at the end of treatment+15

|18|randomised trials|serious|not serious|not serious|not serious|none|330/1591(20.7%)|105/1236(8.5%)|RR 1.96 (1.55 to 2.48)|82 more per 1,000 (from 47 more to 126 more)|$$\oplus\oplus\oplus\bigcirc$$ Moderatea|IMPORTANT| |---|---|---|---|---|---|---|---|---|---|---|---|---|

Number of patients reporting TEAE $^{1,2,3,4,6,7,8,9,10,12,13,15}$

|15|randomised trials|not serious|not serious|not serious|serious|non|1607/2082 (77.2%)|1194/1519 (78.6%)|OR 1.04 (0.81 to 1.35)|7 more per 1,000 (from 38 fewer to 46 more)|$$\oplus\oplus\oplus\bigcirc$$ Moderatea|CRITICAL| |---|---|---|---|---|---|---|---|---|---|---|---|---|

All cause mortality $^{1,2,3,5,8,9,10,11,12,14,15}$

|15|randomised trials|not serious|not serious|not serious|serious:|none|30/2007(1.5%)|19/1513(1.3%)|OR 1.04 (0.57 to 1.89)|0 fewer per 1,000 (from 5 fewer to 11 more)|$$\oplus\oplus\oplus\oplusO$$ Moderate|CRITICAL| |---|---|---|---|---|---|---|---|---|---|---|---|---| |29||||||||||||| |30||||||||||||| |31||||||||||||| |32||||||||||||| |33||||||||||||| |34||||||||||||| |35||||||||||||| |36||||||||||||| |37||||||||||||| |38||||||||||||| |39||||||||||||| |40||||||||||||| |41||||||||||||| |42||||||||||||| |43||||||||||||| |44||||||||||||| |45||||||||||||| |46|||||||||||||

C:confidence interval;HR: hazard ratio;MD: mean difference;OR: odds ratio; RR: risk ratio

Explanations

a.Confidence interval is wide and includes a possible benefit or harm

b. Selective outcome reporting: Inconsistent sampling and reporting across multiple studies. Threshold for resistance varies between organisms.

c.Small number of events and wide confidence interval, that includes large benefit or harm

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European Respiratory Journal

Author(s):James Chalmers and Stefano Alberti

Question: Should macrolides vs No Macrolides be used for Bronchiectasis

Setting: Outpatients with bronchiectasis

Bibliography:

1.Tsang K,Ho Pl,Chan K,et al.A pilot study of low-dose erythromycin in bronchiestasis. Eur Respir J 1999;13:361-4

2.Liu J,Zhong X,He Z,et al.Effect of low-dose, long-term roxithromycin:in airway inflammation and remodeling of stable noncystic fibronbiectasis. Mediatf Inflamm 2014:2014:1-4

3.Wong C, Jayaram L, Karalus N, et al. Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis: the Mediat Inflamm 2014;2014:1-4

4.Sesier DJ, Martin ML, McGuckin MA, et al. Effect of long-term, low-dose erythromycin on pulmonary exacerbations (EMBRACE): a randomised, double-blind, placebo-controlled trial. Lancet 2012;380:660-7

5.Altenburg J, de Graaff CS, Stienstra Y, et al. Effect of azithromycin maintenance treatment on infectious exacerbations among patients with non-cystic fibron bronchictasis: the BLESS randomized controlled trial. JAMA 2013;309:1260-7

6. Diego AD,Milara J,Martinez-Moragon E,et al.Effects of long-term azromycin on airway oxidative stress among patients with non-cystic fibron bronchiectasis: the BAT randomized controlled trial. JAMA 2013;309:1260-7

Lourdesamy Anthony Al,MuthukumarU.Efficacy of azithromycin in the treatment of bronchiectasis in an nocystic fibrosis bronchiectasis: Respirology 2013;18:1056-62

8.Chalmers JD,Boersa W,Longaem M,et al.Long-term macrolide antibiotics for the treatment of bronchiectasis in adults: an individual participant data meta-analysis.Lancet Respir.2019(10:85)2014 Nov;19(8):1178-82. doi:10.1111,res.12375.1056.62

9. Juthong et al. Roxithromycin as Anti-inflammatory Drug Improves Clinical Outcomes in Adult Patients with Bronchiectasis: A Double- Blinded Randomized, Placebo-Controlled Pilot Clinical Trial J Health Sci Med Res 2019;37(3):229-236

|No of studies|Certainty assessment|Certainty assessment|No of patients|No of patients|Effect|Effect|Certainty|Certainty| |---|---|---|---|---|---|---|---|---| |No of studies|Study design|Risk of bias|Inconsistency|Indirectness|Imprecision|Other considerations|Certainty|Certainty| |No of patients with exacerbations1s|||||||||

No of patients with exacerbations1-5

|5|randomised trials|not serious|not serious|not serious|not serious|non serious|none|92/206(44.7%)|138/199(69.3%)|RR 0.64 (0.46 to 0.89)|250 fewer per 1,000 (from 374 fewer to 76 fewer)|$$\oplus\oplus\oplus\oplus\oplus$$ High|CRITICAL| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|

Time to first exacerbation

|2|randomised trials|not serious|not serious|not serious|not serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|

Exacerbaxation frequency+4

|4|randomised trials|not serious|not serious|not serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious|non serious|non-10.81% High|Rate ratio 0.48 (0.37 to 0.62)|Not applicable|$\oplus\oplus\oplus$ High|CRITICAL| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---| |SGRQ total score $2.3.4.6.7.9 $|||||||||||||||||||

SGRQ total score2,3,4,5,6,7,9

|7|randomised trials|serious ${}^{a}$|not serious|not serious|not serious|none|256|252|NA|MD 7.26 lower (10.94 lower to 3.59 lower)|MD 7.26 lower (10.94 lower to 3.59 lower)|CRITICAL| |---|---|---|---|---|---|---|---|---|---|---|---|---| |Antibiotic resistance organisms $_{1,8}$|||||||||||||

|2|randomised trials|serious|not serious|not serious|serious|none|NA/66|NA/67|OR 1.08 (0.22 to 5.19)|Not estimable|$$\oplus\bigcirc\bigcirc\bigcirc$$ Low ${}^{c}$|IMPORTANT| |---|---|---|---|---|---|---|---|---|---|---|---|---|

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Page 101 of 177

European Respiratory Journal

||Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|No of patients|No of patients|Effect|Effect|Certainty|Importance| |---|---|---|---|---|---|---|---|---|---|---|---|---|---| ||No of studies|Study design|Risk of bias|Inconsistency|Indirectness|Imprecision|Other considerations|Macrolides|No Macrolides|Relative (95% CI)|Absolute|Certainty|Importance| |Isolation of new pathogens ${}^{4,5}$|||||||||||||| |2|randomised trials|serious|not serious|not serious|serious|non|19/105 (18.1%)|22/103 (21.4%)|OR 0.82 (0.41 to 1.63)|31 fewer per 1,000 (from 113 fewer to 93 more)|$$\oplus\oplus\oplus$$ Low ${}^{d}$$|IMPORTANT|| |Adverse events ${}^{1,3,4,5,7,9}$|||||||||||||| |6|randomised trials|not serious|not serious|not serious|non serious|98/229 (42.8%)|101/227 (44.5%)|OR 0.86 (0.53 to 1.39)|37 fewer per 1,000 (from 147 fewer to 82 more)|$$\oplus\oplus\oplus$$ Moderate-|CRITICAL||| |Mortality ${}^{4,8}$|Mortality ${}^{4,8}$|Mortality ${}^{4,8}$|Mortality ${}^{4,8}$|Mortality ${}^{4,8}$|Mortality ${}^{4,8}$|Mortality ${}^{4,8}$|Mortality ${}^{4,8}$|Mortality ${}^{4,8}$|Mortality ${}^{4,8}$|Mortality ${}^{4,8}$|Mortality ${}^{4,8}$||| |3|randomised trials|not serious|not serious|not serious|serious|non|2/108 (1.9%)|0/107 (0.0%)|OR 5.63 (0.26 to 121.88)|0 fewer per 1,000 (from 0 fewer to 0 fewer)|$\oplus\oplus\oplus$ Moderate ${}^{4}$|CRITICAL|| |Severe exacerbations ${}^{5}$|||||||||||||| |1|randomised trials|not serious|not serious|not serious|serious|non|1/43 (2.3%)|2/40(5.0%)|OR 0.45 (0.04 to 5.19)|27 fewer per 1,000 (from 48 fewer to 165 more)|$\oplus\oplus\oplus$ Moderate|CRITICAL|| |$$\text{Cl:}\,\text{confidence interval;HR;}\,\text{hazard ratio;MD;mean difference;OR;odds ratio;RR;nk ratio$$|||||||||||||| |Explanations|Explanations|Explanations|Explanations|Explanations|Explanations|Explanations|Explanations|Explanations|Explanations|Explanations|Explanations||| |a. Lack of blinding (De Diego et al and Liu et al). Incomplete accounting of patients and outcome events and selective outcome reporting(Juthong et al). b.Incomplete outcome reporting and possible selective reporting of outcomes|||||||||||||| |c.The confidence interval include both relevant benefits and harms|||||||||||||| |d.This endpoint is highly dependent on systematic monitoring for pathogens which was not protocolised in the studies (Selectiveal correction in the studies (Selective outcome reporting in risk of bias assessment) }$|||||||||||||| |e. Small number of events and wide confidence interval of the overall effect||||||||||||||

||European Respiratory Journal Page 102 of 177|||||||||||||| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---| ||Author(s): Pieter Goeminne Question: Should Long-term non-macrolide oral antibiotics be used compared to no long term oral antibiotics for adult patients with bronchiectasis and a history of exacerbations Setting: Outpatients Bibliography: Bibliography: 1.Currie DC,Garbett ND,Chan KL,et al. Double-blind randomized study of prolonged higher-dose oral amoxycillin in purulent bronchiectasis.Q J Med.1990;76(280):799-816. 2.PROLONGED antibiotic treatment of severe bronchiectasis; a report by a subcommittee of the Antibiotics Clinical Trials (non-tuberculous) Committee of the Medical Research Council. Br Med J.1957;2(5039):255-259.)|||||||||||||| |Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Impact|Certainty|| |Ne of studies|Study design|Risk of bias|Inconsistency|Indirectness|Imprecision|Other considerations|Word|Impact|Certainty|Importance||Impact|Certainty|| |Number of exacerbation1||||||||||||||| |1|randomised trials|serious|not serious|not serious|very serious,b.c||none|-17 patients in the amoxicillin group and 19 in the placebo group - In the intervention group exacerbations were(2(0-7)) and in the placebo group(4(0-9)). - No information is provided if this is median or mean. The methodology mentions only that "The majority of the variables were not normally distributed and therefore group results are expressed as medians and non-parametric tests were used for analysis." - The study clearly states: "after adjusting for the number of exacerbations experienced in the year before the study this difference was not significant."|$$\oplus\bigcirc\bigcirc$$ Very lowc,d.c||CRITICAL|||| |||||||||||||||| |Mortality2||||||||||||||| |||||||||-38 patients on penicillin, 44 patients on oxytetracyclin and 40 patients on placebo. - One patient died in each group.|$$\oplus\bigcirc\bigcirc\bigcirc$$ Very lowc,d||CRITICAL|||| |AB resistance1|AB resistance1|AB resistance1|AB resistance1|AB resistance1|AB resistance1|AB resistance1|AB resistance1|AB resistance1|AB resistance1|AB resistance1|AB resistance1|||| ||1|randomised trials|serious|not serious|not serious|very seriousc||none|-17 patients in the amoxicillin group and 19 in the placebo group - Five events of AB resistance were recorded in the amoxicillin group(3 H.infl.resistances and 2 Gram negative resistances) whereas 2 events were seen in the placebo group(1 H.infl resistance and 1 Gram negative resistance).|±000 Very lowc,d||IMPORTANT||| |New PPM1|New PPM1|New PPM1|New PPM1|New PPM1|New PPM1|New PPM1|New PPM1|New PPM1|New PPM1|New PPM1|New PPM1|||| |Downloaded from https://publications.ersnet.org on September 29, 2025 by guest. Please see licensing information on first page for reuse rights. 47|||||||||||||||

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European Respiratory Journal

|12|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Impact|Certainty|Importance|| |---|---|---|---|---|---|---|---|---|---|---| |12|Ne of studies|Study design|Risk of bias|Inconsistency|Indirectness|Imprecision|Impact|Certainty|Importance|Other considerations| |4|1|randomised trials|serious|not serious|not serious|very serious|-17 patients in the amoxicillin group 19 in the placebo group|-17 patients in the amoxicillin group 19 in the placebo group|Very low|IMPORTANT| |5||||||||||| |6|randomised trials|serious|not serious|not serious|very serious|-11 events of new PPM were recorded in the amoxicillin group (6 non-Pseudomonas Gram velocities, 4 Pseudomonas and 1 Moraxella) whereas 8 events of new PPM where recorded negatives, 4 Pseudomonas and 1 N of the placebo group (3 non-Pseudomonas Gram negatives, 3 Moraxella, 1 Pseudomonas and 1 Staph aureus).|-11 events of new PPM were recorded in the placebo group (3 Non-Pseudomonas Gram negatives, 3 Moraxella, 1 Pseudomonas and 1 Staph aureus).|Very low||| |8||||||||||| |2|randomised trials|serious|not serious|serious|serious|—091 patients in the amoxicillin group 19 in the placebo group A total of 34 AEs in the amoxicillin group and 20 AEs in the control group.|Very low||Critical|| |2|randomised trials|serious|not serious|serious|none|-Curie et al.: 16 patients in the amoxicillin group and 19 in the placebo group - Scadding et al.:36 in the penicillin group; 40 in the oxytetracycin group and 36 in the placebo group al:36 in the penicillin group; 40 in the oxytetracycin group and 36 in the placebo group.|Only over||Critical||

Symptoms % sputum volume reduction*1,2

|2|randomised trials|serious$^{a8}$|not serious|serious$^{a1}|nonone|- Curie et al.:16 patients in the amoxicillin group and 19 in the placebo group- Scadding et al.:36 in the penicillin group; 40 in the oxytetracycin group and 36 in the placebo group.|$$\Box\bigcirc\bigcirc$$ $$\forall\text{ very}^{a.c.}$$|CRITICAL|| |---|---|---|---|---|---|---|---|---|---| |45|||||||||| |46|||||||||| |47||||||||||

|1|randomised trials|serious$|not serious$|very serious$|very serious$|none|- Scadding et al.: 36 in the penicillin group;40 in the oxytetracyclin group and 36 in the placebo group|$$\oplus\bigcirc\bigcirc\bigcirc$$ Very low|CRITICAL|| |---|---|---|---|---|---|---|---|---|---|---| |4|||||||||||

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|12 European Respiratory Journal Impact Certainty Importance|Certainty|Importance|||||||||||||| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---| |12 European Respiratory Journal Impact Certainty Importance|Certainty|Importance|No of studies|Study design|Risk of bias|Inconsistency|Indirectness|Imprecision|Other considerations||||||| |QOL - not reported|QOL - not reported|QOL - not reported|QOL - not reported|QOL - not reported|QOL - not reported|QOL - not reported|QOL - not reported|QOL - not reported|QOL - not reported|QOL - not reported|QOL - not reported|QOL - not reported|QOL - not reported||| ||0||-|-|-|-|-|-||No data were reported for this outcome||CRITICAL|||| |Severe exacerbations- not reported|||||||||||||||| ||0||-|-|-|-|-|-||No data were reported for this outcome||CRITICAL|||| |$$\text{Cl: confidence interval}$$|||||||||||||||| |Explanations|Explanations|Explanations|Explanations|Explanations|Explanations|Explanations|Explanations|Explanations|Explanations|Explanations|Explanations|Explanations|Explanations||| ||a. There's no data on how randomization was performed.||||||||||||||| ||b. Unclear reporting of the data||||||||||||||| ||c. Relatively few patients and/or few events||||||||||||||| ||d. One included study only but with no reported overall difference between groups||||||||||||||| ||e. One patient 15 yo died of fibrocystic disease of the pancreas, suggesting cystic fibrosis as an underlying cause.||||||||||||||| ||f. Pooling of data difficult or not possible, so we cannot judge the precision of the overall effect||||||||||||||| ||g. No use of validated outcome measure||||||||||||||| ||||||||||||||||| |Downloaded from https://publications.ersnet.org on September 29, 2025 by guest. Please see licensing information on first page for reuse rights.||||||||||||||||

|European Respiratory Journal|||||||||||||||| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---| |Question:Should Eradication treatment compared to no eradication treatment be used for Bronchicasties|||||||||||||||| |Setting: patients with new or recurrent isolation of a pathogenic microorganism|||||||||||||||| |Bibliography:|Bibliography:|Bibliography:|Bibliography:|Bibliography:|Bibliography:|Bibliography:|Bibliography:|Bibliography:|Bibliography:|Bibliography:|Bibliography:|Bibliography:|Bibliography:|Bibliography:|Bibliography:| |1|Pieters,ABaker M,Hoek RAS,et al.The clinical impact of Pseudomonas aeruginosa eradication in bronchieastasis in a Dutch referral centre.Eur Respir J 2019;53:1802081.doi:10.1183/13993003.02081-2018|1. Pieters A,Bakker M,Hoek RAS,et al.The clinical impact of Pseudomonas aeruginosa eradication in bronchieastasis in a Dutch referral centre.Eur Respir J 2019;53:1802081.doi:10.1183/13993003.02081-2018|||||||||||||| |2|White L,Mirrani G,Grover M,et al.Outcomes of Pseudomonas eradication therapy in patients with non-cystic fibrosis bronchiefasis. Respir Med 2012;106:356-360.doi:10.1016/j.mred.2011.11.018|1.2.2.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3||||||||||||||

European Respiratory Journal

Page 106 of 177

|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|Certainty assessment|No of patients|No of patients|Effect|Effect|Certainty|Importance| |---|---|---|---|---|---|---|---|---|---|---|---|---| |Ne of studies|Study design|Risk of bias|Inconsistency|Indirectness|Imprecision|Other considerations|Pseudomonas eradication treatment|no eradication (95% CI)|Relative (95% CI)|Absolute|Certainty|Importance| |2|non- randomised studies|very serious${}^{a,d}$|not serious|serious|serious|||Valieres et al reported respiratory symptoms associated with nebulised colistimethate sodium were infrequent as only two patients had to prematurely discontinue the inhaled treatment out of 54 patients.||$$\oplus\bigcirc\bigcirc$$ $$\text{Very low}^{a,b}$$|$$\text{CRITICAL}$$|| |Antibiotic resistance${}^{2,8}$|||||||||||||

Antibiotic resistance?#

|2|non-randomised studies|very serious${}^{*}$.*|not serious|serious${}^{b}$|serious${}^{b}$|||Rported in one study(White et al). In 6/11 patients, Pseudomonas remained fully sensitive (including to ciprofloxacin) following treatment. In four patients, new antibiotic resistance occurred: azretonam(n=1), ciprofloxacin(n=1), ciprofloxacin and gentamicin(n=1), amikacin and gentamicin(n=1).|$$\oplus\bigcirc\bigcirc\bigcirc\bigcirc$$ Very low ${}^{b+}$$|IMPORTANT|| |---|---|---|---|---|---|---|---|---|---|---|---| |||||||||||||

Mortality

|||||||No data was identified|||CRITICAL| |---|---|---|---|---|---|---|---|---|---|

C: confidence interval; MD: mean difference

Explanations

a.Method of data collection is unclear and it is unclear whether it is standardised between time periods.

b. this is a before and after study rather than a parallel group study

c.No measure of precision is included.

d.No standardisation of testing to ensure detection of PA in most studies.

e.high risk of reporting bias and selective reporting

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*This paper contains a way for a certain time, and it is a certain as a given time, and it is a certain as a given time.

|IN1V 20|8|6|8|8|8|8|8|8|8|8| |---|---|---|---|---|---|---|---|---|---|---| |IN1V 30|0000|0|0|0|0|0|0|0|0|0| |IN1V 30|0|0|0|0|0|0|0|0|0|0| |IN1V 30|0|0|0|0|0|0|0|0|0|0| |IN1V 30|0|0|0|0|0|0|0|0|0|0| |IN1V 30|0|0|0|0|0|0|0|0|0|0| |IN1V 30|0|0|0|0|0|0|0|0|0|0| |IN1V 30|0|0|0|0|0|0|0|0|0|0| |IN1V 30|0|0|0|0|0|0|0|0|0|0| |IN1V 30|0|0|0|0|0|0|0|0|0|0| |IN1V 30|0|0|0|0|0|0|0|0|0|0| |IN1V 30|0|0|0|0|0|0|0|0|0|0| |IN1V 30|0|0|0|0|0|0|0|0|0|0|

:

pseudo'galon' gasei pase, which is an ambient energy or no longer the system of the system.

s\n$+1000$

|||||||||||| |---|---|---|---|---|---|---|---|---|---|---| |||||||||||| |||||||||||| |||||||||||| |||||||||||| |||||||||||| |||||||||||| |||||||||||| |||||||||||| |||||||||||| |||||||||||| |||||||||||| |||||||||||| |||||||||||| |||||||||||| |||||||||||| ||||||||||||

|1|e. Confidence interval is wide and includes clinically relevant harm| |---|---| |2|f. Incomplete outcome reporting| |3|| |4|| |5|| |6|| |7|| |8|| |9|| |10|| |11|| |12|| |13|| |14|| |15|| |16|| |17|| |18|| |19|| |20|| |21|| |22|| |23|| |24|| |25|| |26|| |27|| |28|| |29|| |30|| |31|| |32|| |33|| |34|| |35|| |36|| |37|| |38|| |39|| |40|| |41|| |42|| |43|| |44|| |45|| |46|| |28|| |47|| |||

||European Respiratory Journal|||||||||||||||||||||||| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---| ||Question: Pulmonary rehabilitation (exercise training) compared to No PR (usual care) for Bronchiectasis|Question: Pulmonary rehabilitation (exercise training) compared to No PR (usual care) for Bronchiectasis|Page 110 of 177|Page 110 of 177|Page 110 of 177|Page 110 of 177|Page 110 of 177|Page 110 of 177|Page 110 of 177|Page 110 of 177|Page 110 of 177|Page 110 of 177|Page 110 of 177|||||||||||| |5|8|Question: Pulmonary rehabilitation (exercise training) compared to No PR (usual care) for Bronchiectasis|Bibliography: <|Lee,A.L.,H. C.,J. Kinsens, N.,Jenkins,S.,McDonald,C.F.,Burge,A.T.,Rautela,L.,Stirling,R.G.,Thompson,P.J.,Holland,A.E.,E. The short and long term effects of exercise training in non-cystic fibrosis bronchiectasis-a randomised controlled trial Respir Res; Apr 15 2014. 2.Cedeno de Jesus,S.,Amaladana Pacheco, V.,Vallo Morales,A.MurizRodriguez,A.M.,Ayerbe Garcia,R.,Armedio-Munoz,A.E.,Exercise Capacity and Physical Activity in Non-Cystic Fibrosis Bronchiectasis after a Pulmonary Rehabilitation Home-Based Programme: A Randomised Controlled Trial.Int J Environ Res Public Health; Sep 3 2022. 3.Araujo,A.S.,Figueiredo,M.R.,Lomonaco,I.,Lundgren,F.,Mesquita,R.,Pereira,E.D.B.Effects of Pulmonary Rehabilitation on Systemic Inflammation and Exercise Capacity in Bronchiectasis: A Randomized Controlled Trial.Lung; Jun 2014. 2.Cedeno de Jesus,R.,Aill,S.L..Exercise and Inspiratory muscle training in patients with bronchiectasis.Thorax;Nov 2005. 5.Amalad,S.,Pidush,M.K.,Kope,L.,Pollock,W.,Stevenson,L.M.,Pentland,J.L.,Tumbull,K.,Mac Quarie,S.,Hill,L.,A pilot study of pulmonary rehabilitation and chest physiotherapy versus chest physiotherapy alone in bronchiectasis.Respir Med; Dec 2012. 2.Jose,A.,Holland,A.E.,Selman,J.P.,R.,de Camargo,C.O.,Fonseca,D.S.,Athanazio,R.A.,Rached,S.Z.,Cukier,A.,Stelmach,R.,Del Corso,S.,Home-based pulmonary rehabilitation in people with bronchiectasis: a randomised controlled trial.ERJ Open Res; Apr 2021. 2.Pulmonary Rehabilitation versus No Pulmonary Rehabilitation for Bronchiectasis. Cochrane Database of Systematic Reviews||||||||||||||||||||| |||||||||||||||||||||||||| |No of studies|No of studies|Study design|Risk of bias|Inconsistency|Inditness|Indirectness|Imprecision|Other considerations|Pulmonary rehabilitation (exercise training)|No PR (usual care)|Effect Relative (95% CI)|Certainty|Certainty|Importance||||||||||| |Exercise capacity (6WT,M)|after intervention1,2.3|||||||||||||||||||||||| |3|randomised trials|serious*|not serious|not serious|not serious|not serious|none|73|75|not applicable|MD 41.13 higher (28.74 higher to 53.53 higher)|||||||||||||| |Exercise capacity (6WT,M)|at the end of follow-up|||||||||||||||||||||||| |1|randomised trials|not serious|not serious|not serious|non serious||||none|30|25|not applicable|MD 6.74 lower (29.61 lower to 16.13 higher)||IMPORTANT|||||||||| |28||||||||||||||||||||||||| |Exercise capacity (ISWT,m) after the end of follow-up1||||||||||||||||||||||||| |4|randomised trials|serious*|not serious||not serious|not serious|non serious||86|91|not applicable|MD 72.83 higher (51.44 higher to 94.23 higher)||$\oplus\oplus\bigcirc$ Moderate||IMPORTANT||||||||| |Exercise capacity (ISWT,m) at the end of follow-up1||||||||||||||||||||||||| |2|randomised trials|serious*|not serious|not serious|not serious|Serious*||none|42|40|not applicable|MD 39.41 higher (33.02 lower to 111.83 higher)||$\oplus\oplus\bigcirc$ Low|IMPORTANT||||||||||

,which is, the effect of the effect of the effect on the same time, is a significant difference, and the effect of the effect on the same time, is a significant difference, and the effect of the effect on the same time, is a significant difference, and the effect of the effect on the same time, is a significant difference, and the effect of the effect on the same time, is a significant difference, and the effect of the effect on the same time, is a significant difference, and the effect of the effect on the same time, is a significant difference, and the effect of the effect on the same time, is a significant difference, and the effect of the effect on the same time, is a significant difference, and the effect of the effect on the same time, is a significant difference, and the effect of the effect on the same time, is a significant difference, and the effect of the effect on the same time, is a significant difference, and the effect of the effect on the same time, is a significant difference, and the effect of the effect on the same time, is a significant difference, and the effect of the effect on the same time, is a significant difference, and the effect of the effect on the same time, is a significant difference, and the effect of the effect on the same time, is a significant difference, and the effect of the effect on the same time, is a significant difference, and the eff

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European Respiratory Journal

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|Ne of patients|Ne of patients|Ne of patients|Ne of patients|Ne of patients|Ne of patients|Ne of patients|Ne of patients|Ne of patients|Ne of patients|Ne of patients|Ne of patients|Ne of patients|Ne of patients|Certainty|Certainty| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---| |Ne of patients|Ne of patients|Ne of patients|Ne of patients|Ne of patients|Ne of patients|Ne of patients|Ne of patients|Ne of patients|Ne of patients|Ne of patients|Ne of patients|Ne of patients|Ne of patients|Certainty|Certainty| |1|randomised trials|very serious${}^{c}$|not serious|not serious|Not serious${}^{b}$|Serious${}^{b}$|none|27|28|not applicable|MD 3.6 higher (3.18 lower to 10.38 higher)|$\oplus\bigcirc\bigcirc$ Very low${}^{c}$|CRITICAL||| |Symptoms(fatigue-FSS) after the intervention${}^{3}$|||||||||||||||| |1|randomised trials|serious${}^{a}$|not serious|not serious|Serious${}^{b}$|none|20|21|not applicable|MD 1.3 lower (1.55 lower to 1.05 lower)|$\oplus\bigcirc\bigcirc$ Low ${}^{a}$|CRITICAL|||| |Exacerbations (% participants with at least one exacerbation during follow-up)|||||||||||||||| |1|randomised trials|serious${}^{a}$|not serious|not serious|Serious${}^{b}$|none|12/30 (40.0%)|18/25 (72.0%)|OR 0.26 (0.08 to 0.81)|319 fewer per 1,000 (from 549 fewer to 44 fewer)|$\oplus\bigcirc\bigcirc$ Low ${}^{a}$|CRITICAL|||| |Mortality(event) during the follow-up ${}^{11}$|||||||||||||||| |1|randomised trials|not serious|not serious|not serious|very serious${}^{a}$|none|0/30(0.0%)|1/25 (4.0%)|OR 0.27 (0.01 to 6.87)|29 fewer per 1,000 (from 40 fewer to 183 more)|$\oplus\bigcirc\bigcirc$ Low ${}^{e}$|CRITICAL|||| |Severe exacerbation|Severe exacerbation|Severe exacerbation|Severe exacerbation|Severe exacerbation|Severe exacerbation|Severe exacerbation|Severe exacerbation|Severe exacerbation|Severe exacerbation|Severe exacerbation|Severe exacerbation|Severe exacerbation|Severe exacerbation||| |0|||||||No data identified for this outcome|||||||||

CI: confidence interval; MD: mean difference; OR: odds ratio

Explanations

a. All of the available studies have a lack of blinding

b.The 95% confidence interval crosses the line of no clinically significant effect

c.High risk of attrition bias was detected, as one study only 37/66 participants allocated to the intervention provided 6 month data

d.The two included studies show opposite conclusions with no overlap of the Cls.

e.Downgraded twice for imprecision as based on a single event therefore no meaningful conclusions can be reached

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Evidence to Decisions(EtD) framework

European Respiratory Journal

Narrative question: 1. How can underlying causes of bronchiectasis be identified and how can the severity,comorbidities and other treatable traits be evaluated

|Domain|Judgement|Research evidence|Additional considerations| |---|---|---|---| |Priority|O No|No direct research evidence on the priority was identified but the large number of publications retrieved would indicate this area is considered important by the research community.|Causes| |Is the Problem a priority|O Probably no|No direct research evidence on the priority was identified but the large number of publications retrieved would indicate this area is considered important by the research community.|● Identifying the cause of bronchiectasis is regarded as a priority as it can change management and identifying the cause is desirable for patients.| ||● Yes||Severity| ||O Varies||Bronchiectasis is a heterogeneous disease with a wide spectrum of severities and therefore severity assessment and prognostication is a priority to guide management| ||O Don't know||Co-morbidity ● Evidence suggests co-morbidities are common and impact on mortality and quality of life making identification and treatment of co-morbidities potentially important.| |Certainty of evidence|What is the overall certainty of the evidence of effects? o Very Low o Low|There is a moderate degree of certainty because of the high level of consistency in the literature between studies on the frequency of underlying causes, the high level of severity assessment tools and associated prognostic features and publications related to comorbidities.|Causes| ||O Very Low o Low||is large and there is consistency between studies(with some geographical variation.| ||O Low o Moderate||Severity| ||O High||The evidence for most prognostic markers is very strong and consistent and the severity assessment tools (particularly BSI) are well validated.| |32||o High|Co-morbidity The relationship between co-morbidities and poor outcomes is well established with a high quality and consistency of evidence even data are from observational studies.| |35|||Treatable traits As above.| |36|||| |37|||| |38|||| |39|||| |40|||| |41|||| |42|||| |43|||| |44|||| |45|||| |46||||

|1|Values|Is there important uncertainty about or variability in how much people value the main outcomes? o Important uncertainty or variability|Causes There is Esopropereatory law onmmatical community about the value of aetiological testing. The main question is what to test for and when Patients value identifying the cause highly. Severity ● There is no uncertainty or variability in the need to identify patients at risk of worse outcome. How best to do this and whether to use scoring or individual risk factors is debated.|Input from the patient members of the guideline panel indicates Page 114 of 177| |---|---|---|---|---| |2||||| |3|||Severity ● There is no uncertainty or variability in the need to identify patients at risk of worse outcome. How best to do this and whether to use scoring or individual risk factors is debated.|holistic management taking into account health issues not related directly to bronchiectasis is considered highly important.| |4||O Important uncertainty or variability|Co-morbidity ● There is no uncertainty about the need to manage patient holistically and to treat underlying conditions. The extent to which patients should be screened as part of routine BE care may be debated.|| |5||O Possibly important uncertainty or variability|There is no uncertainty about the need to manage patient holistically and to treat underlying conditions. The extent to which patients should be screened as part of routine BE care may be debated.|| |10||XProbably no important uncertainty or variability or variability are not important uncertainty or variability|Treatable traits The utility of the treatable traits concept can be debated but the principle that patients with bronchiectasis should be treated in a personalized way is not debated.|| |11||||| |12||XProbably no important uncertainty or variability|Treatable traits The utility of the treatable traits concept can be debated but the principle that patients with bronchiectasis should be treated in a personalized way is not debated.|Causes - The fact that investigation of underlying causes can lead to highly effective treatments strongly favours underlying cause testing in a standardized way. Exactly how to do this and which tests to recommend can be debated but the basic principle is strongly favoured by the evidence.| |15||||| |16||O Still important uncertainty or variability|Severity ● Better targeting of treatment towards patients at higher risk of complications should result in better cost-effectiveness of treatment|- Evidence strongly favours classifying patients by their risk of poor or good in the best method to do this can be debated but the principle is not debated.| |17||X Large|Co-morbidity ● Several co-morbidities are increased in people with bronchiectasis and are associated with mortality or quality of life. Examples include cardiovascular disease, osteoporosis, depression, anxiety and rhinosinusitis.These have treatments or preventative measures available the use of which may bring desirable benefits|Co-morbidity Evidence strongly favours the need to identify and treat co-morbid conditions. Treatable traits As above, the evidence strongly favours identifying and treating appropriate traits.| |41||o Don't know|Treatable traits ● Literature search identifies a number of aetiologies and co-morbidities as treatable traits and also identifies symptoms,|| |42||||| |43||||| |44||||| |45||||| |46|||||

|1|10|2|3|| |---|---|---|---|---| |2||1|1|| |3||1|1|| |4||1|1|| |5||1|1|| |6|||1|| |7||X Moderate|Severity|| |8||OLarge|● Severity assessment tools are not perfect and so potential undesirable effects of these tools include misclassifying patients resulting in under/over treatment.|| |10||||| |11|||Co-morbidity|| |12|||There are few if any undesirable effects to investigating co-morbidities.|| |13|||● Treatable traits|| |14||Currently most treatable traits are not supported by prospective clinical trial evidence and so when specific traits are used to guide treatment they may lead to inappropriate treatment or an increased use of medication in some circumstances||| |15||||| |16||||| |17||||| |18||||| |19||||| |10||||| |20||||| |21||||| |22||||| |23||||| |24||||| |25||||| |26||||| |27||||| |28||||| |29||||| |30||||| |31||||| |32||||| |33||||| |34||||| |35||||| |36||||| |37||||| |38||||| |39||||| |30||||| |31||||| |40||||| |39||||| |40||||| |41||||| |42||||| |43||||| |44||||| |45||||| |46||||| |||||| |||||| |||||| |Downloaded from https://publications||Obps on September 29, 2025|Use please see licensing information on first page for reuse rights.|Causes Testing is current guideline practice and is accepted (wanted) by patients| |||||| |||||| |||||| |$$\begin{array}{l}\\ \\ \\ \\ \\ \\ \\ \\ \\ \\ \end{array}$$|||||

||XYes o Varies|European Respiratory Journal|Treatable traits Precision medicine is generally popular/accepted by patients and clinRage 116 of 1|| |---|---|---|---|---| ||o Don't know|European Respiratory Journal||| |Feasibility|Is the intervention Feasible to implement ?|We did not specifically look for studies on feasibility but these proposed interventions are considered standard of care in many centres and are therefore considered feasible.|The answer to this question varies depending on the intervention recommended Causes, Routine testing for ABPA, immunoglobulins, NTM= highly feasible Routine testing for CF/PCD- not feasible Targeted testing for CF/PCD= feasible with some caveats Severity|| |10|o Probably yes|||| |12|oYes|||| |14|X Varies|||| |15|o Don't know|||| |16||||| |17||||| |18||||| |19||||| |20||||| |21||||Causes| |22||||| |23||||| |24||||| |25||||| |26||||| |27||||| |28||||| |29||||| |30||||| |31||||| |32||||| |33||||| |34||||| |35||||| |36||||| |37||||Treatable traits As abov| |38||||| |39||||| |40||||| |41||||| |42||||| |43||||| |44||||| |45||||| |46|||||

|1|||European Respiratory Journal|Severity - Likely to be high cost effective Co-morbidity Likely to be highly cost effective Treatable traits| |---|---|---|---|---| |2|Certainty of the evidence of required resources|X Very low o Low o Moderate o High o No included studies|We did not specifically look for studies on required resources.The included studies in our review did not have any data for any of the aspects of this question that directly addressed the costs or cost-effectiveness of different screening pathways. We base our assessment on clinical experience.|| |8||||| |9||||| |10||||| |11||||| |12||||| |13||||| |14||||| |15||||| |16||||| |17||||| |18||||| |33||||| |34||||| |35||||| |36||||| |37||||| |38||||| |39||||| |30||||| |41||||| |42||||| |43||||| |44||||| |45||||| |46|||||

||● The assessments described here including considering the underlying cause, co-morbidities, disease activity and treatable traits, should be considered at all patient visits and not just at diagnEucean Respiratory Journal| |---|---| |Justification|The recommendation to test for underlying causes in bronchlocasis is justified by the potential benefits of identifying treatable conditions that can improve patient outcomes. Despite potential increases in healthcare costs and complexity, the prioritisation of diagnosing treatable underlying theoretical conditions that can improve patient outcomes. Despite A1ATD, CF and PCD to patients with suggestive clinical features emphasizes a targeted diagnostic approach that balances the need for comprehensive evaluation with the risk of excessive testing burden.| |Justification|Assessing disease severity is essential to ensure a standardised evaluation of bronchiocasis, facilitating appropriate management strategies. Additionally, recognising and treating comorbidities aligns with a holistic approach to patient care, ultimately improving clinical outcomes.| ||The concept of treatable traits emphasizes the importance of a personalized approach to the treatment of bronchiocasis. Therapeties targeting the underlying cause, associated co-morbidities, and key disease features(infection, impaired mucociliary clearance, inflammation etc) are dependent on a comprehensive assessment of the patient to identify treatable| |Subgroup considerations|Age: Co-morbidities increase with age, while CF and PCD are less likely as a setiology as patients get older therefore testing approaches will change with age Sex: largely unaffected Region: Some aetologies are more common in specific regions. ABPA is believed to vary geographically (although no data were identified to support this). CF is more common in white European patients. PCD is more common in some populations, particular where there is consanguinity. Testing facilities and capabilities vary by region. Microbiology varies by region| |Implementation consideration|Implementation of testing for underlying causes in bronchocasis requires a structured approach to address several challenges, including regional disparities in diagnostic capabilities, in many regions due to limited access to specialized diagnostic facilities. The evidence for the treatment of certain treatable causes (particularly PCD) is difficult to implement the treatment of certain treatable traits (e.g cardiovascular disease secondary prevention) is further testing may be appropriate. An example of this is immunodeficiency. Low immunoglobulins/functional antibodies may detect a large number of immunodeficiencies but patients should be referred to an immunologist if they have features that suggest immunodeficiency even if immunoglobulins are normal.| |Monitoring and evaluation|The process of aetological testing is typically undertaken at diagnosis. It is important to emphasise this is an ongoing process - if patients clinical features change such that they suggest a new diagnosis then testing should be reviewed. Furthermore patients who have been previously classified as having one aetiology (particularly idiopathic/postinfective) who although formalized severity assessment is recommended at diagnosis it should be noted that this is an ongoing process and an assessment of future risk should be a key part of every review in a patient with bronchiasis.| |Research priorities|A large scale study performing genetic testing for PCD and cystic fibrosis is required to determine the true prevalence of these conditions in adult bronchiasis and to develop optimal screening strategies Studies utilizing comprehensive aetiological testing approaches in different regions/countries are required to determine if the recommended screening strategy outlined here is appropriate globally|

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PICO QUESTION 1

Should airway clearance techniques be used(compared to no airway clearance techniques) in adults with bronchiectasis?POPULATION:Adults with bronchiectasis

ASSESSMENT

|Problem Is the problem a priority?||| |---|---|---| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| |o No o Probably no O Probably yes X Yes o Varies o Don't know|The efficacy of airway clearance techniques has been identified as important for patients and for clinicians|A number of studies have investigated different airway clearance techniques and there is high variability in their selection and accessibility across Europe and worldwide in practice| |Desirable Effects How substantial are the desirable anticipated effects?||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| |o Trivial o Small X Moderate o Large|There is a clinically significant improvement in the SGRQ and LCQ scores as well as mMRC dyspnoea score indicating improved quality of life, symptoms and performance status in people receiving airway clearance techniques. Effects on exacerbations are less clear.|Most studies are short term, although one longer term study over 1 year shows improved|

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|European Respiratory Journal Page 120 of 177|||| |---|---|---|---| |o Varies o Don't know||quality of life and reduced exacerbations.|| |Undesirable Effects How substantial are the undesirable anticipated effects?|||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS|| |o Large o Moderate o Small oVtrial X Don't know|There were no studies identified that examined undesirable effects, adverse effects or patient burden related to this intervention.|The major undesirable effect reported by patients is the burden of treatment. Some techniques e.g postural techniques may exacerbate conditions like gastroesophageal reflux.|| ||||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS|| |X Very low o Low o Moderate o High o No included studies|Based on GRADE assessment the certainty of evidence is very low. This takes into account that outcomes have a high degree of imprecision and other reasons for downgrading.||| |Values Is there important uncertainty about or variability in how much people value the main outcomes?|||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS|| |o Important uncertainty or variability important 0 Possibly important 0chertainty or Probably no important uncertainty or variability X No important 0chertainty or variability|We did not specifically look for studies addressing patient values|Patients and the panel consistently rated the main outcomes (exacerbations, quality of life and symptoms) as critical.There was more uncertainty around the importance of sputum volume and dyspnea in the absence of other outcomes|| |Balance of effects Does the balance between desirable and undesirable effects favor the intervention or the comparison?||||

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|JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| |---|---|---| |o Favors the comparison o Probably favors the comparison o Does not favor either the intervention or the comparison favors the o Probably favors the intervention o Varies o Don't know|The potential benefit associated with treatment in terms of quality of life and symptoms combined with the fact that this intervention has no known adverse effects favours the intervention|Patient members of the panel consider that the beneficial effects outweigh the treatment burden considerations.| |Resources required How large are the resource requirements(costs)?||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| |o Large costs o Moderate costs o Negligible costs and savings o Moderate savings o Varies X Don't know|We did not look for studies that examined the resources required.|It is known that the intervention requires physiotherapist availability and resource.Resources will vary depending on whether manual techniques or devices are used| |Certainty of evidence of required resources What is the certainty of the evidence of resource requirements(costs)?||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| |o Very low o Low o Moderate o High X No included studies|There were no included studies|| |Cost effectiveness|Cost effectiveness|Cost effectiveness|

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||JUDGEMENT RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS|| |---|---|---|---| |2|o Favors the comparison o Probably favors the comparison o Does not favor either the intervention or the comparison o Probably favors the intervention o Favors the intervention o Varies X No included studies|We did not look for studies that examined the cost effectiveness of the intervention|no additional considerations| |2|o Favors the comparison o Probably favors the comparison o Does not favor either the intervention or the comparison o Probably favors the intervention o Favors the intervention o Varies X No included studies||| |Equity What would be the impact on health equity?|||| |JUDGEMENT|RESEARCH EVIDENCE||ADDITIONAL CONSIDERATIONS| |o Reduced o Probably reduced o Probably no impact X Probably increased o Varies o Don't know|We did not look for studies assessing health equity||Airway clearance is performed by the patient themselves and is a low cost intervention if performed by the patient without equipment. Nevertheless a trained healthcare professional is usually required to teach the patient. Therefore it may be assumed that widespread use of airway clearance would promote health equity.| |Acceptability Is the intervention acceptable to key stakeholders?|||| |JUDGEMENT|RESEARCH EVIDENCE||ADDITIONAL CONSIDERATIONS| |o No o Probably no Yes yes X Yes o Varies o Don't know||The studies identified show a high uptake and persistence with airway clearance suggesting it is acceptable no Probably X Yes o Varies o Don't know|Patient members of the panel indicate that airway clearance is acceptable and that the comparator may not be acceptable.| |Feasibility is the intervention feasible to implement?||||

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|JUDGEMENT|RESEARCH EVIDENCE||ADDITIONAL CONSIDERATIONS| |---|---|---|---| |o No o Probably no o Probably yes yes X Yes o Varies o Don't know|No feasibility issues were identified||Airway clearance is widely used and is feasible to implement in real life practice.|

SUMMARY OF JUDGEMENTS

||JUDGEMENT|JUDGEMENT|JUDGEMENT|JUDGEMENT|JUDGEMENT|JUDGEMENT|JUDGEMENT| |---|---|---|---|---|---|---|---| ||PROBLEM|No|Probably no|Probably yes|Yes|Varies|Don't know| |DESIRABLE EFFECTS|Trivial|Small|Moderate|Large||Varies|Don't know| |UNDESIRABLE EFFECTS|Large|Moderate|Small|Trivial||Varies|Don't know| |CERTAITY OF EVIDENCE|Very low|Low|Moderate|High|||No included studies| |VALUES|Important uncertainty or variability|Possibly important uncertainty or variability|Probably no important uncertainty or variability|No important uncertainty or variability|||| |BALANCE OF EFFECTS|Favors the comparison|Probably favors the comparison|Does not favor either the intervention or the comparison|Probably favors the intervention|Favors the intervention|Varies|Don't know| |RESOURCES REQUIRED|Large costs|Moderate costs|Negligible costs and savings|Moderate savings|Large savings|Varies|Don't know| |CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES|Very low|Low|Moderate|High|||No included studies| |Cost effectiveness|Favors the comparison|Probably favors the comparison|Does not favor either the intervention or the comparison|Probably favors the intervention|Favors the intervention|Varies|No included studies| |EQUITY|Reduced|Probably reduced|Probably no impact|Probably increased|Increased|Varies|Don't know| |ACCEPTABILITY|No|Probably no|Probably yes|Yes||Varies|Don't know| |FEASIBILITY|No|Probably no|Probably yes|Yes||Varies|Don't know|

TYPE OF RECOMMENDATION

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1 2 4 5 6 7 8 9 10 10 11 12 13 14 15 16 7 18 19 20 21 22 23 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 41 42 43 44 45 46 47 48 49 50 51 52 51 53 54 55 56 57 58 59 60

|Strong recommendation against the intervention|Conditional recommendation against the intervention|Conditional recommendation for either the intervention or the comparison|Conditional recommendation for the intervention|Strong recommendation for the intervention| |---|---|---|---|---| ||||O|X|

CONCLUSIONS

Recommendation

Recommendation

We recommend that patients with bronchiectasis should be taught airway clearance techniques(strong recommendation for the intervention, very low certainty of evidence)

Remarks

Airway clearance techniques(ACTs) are best taught by a respiratory physiotherapy with appropriate experience.

There is no evidence that one technique is superior to another and, therefore, treatment should be personalized.

Airway clearance devices may be used to support manual ACTs.

Previous ERS guidelines limited ACTs to patients with chronic productive cough. The current recommendation acknowledges that some patients with a dry cough, particularly those with mucus plugging on chest CT, may benefit from ACTs. Instruction in ACTs may also assist patients during periods of increased symptoms, such as exacerbations.

Justification

ACTs are associated with improved quality of life and symptoms, and may reduce exacerbations. Airway clearance is a key component of daily bronchiectasis management. Despite the low certainty of evidence, the panel issued a strong recommendation based on the following: i) ACTs are self-administered, low-cost, and accessible; ii) Patients widely recognise their benefits; iii) The recommendation was strongly supported by patient representatives. Although adverse effects and harms were not systematically reported or collected, ACTs are widely believed to be safe and low risk of adverse events. These factors outweigh the limitations of the evidence base and highlight a need for broader implementation. Airway clearance is underutilized in clinical practice, and this recommendation should encourage increased uptake among healthcare professionals and policy.

Subgroup considerations

There is no evidence of subgroup effects in the data identified. The studies to date include a wide spectrum of bronchiectasis patients suggesting broad efficacy

Implementation considerations

Airway clearance techniques require appropriate training and personalization of the techniques. Not all patients will have access to a specialist respiratory physiotherapist. No studies were identified on optimal delivery of the intervention.

Monitoring and evaluation

Patients who have received training in airway clearance techniques may require additional review to ensure the techniques are still performed correctly, are suitable to patient needs and/or to modify techniques if the disease changes.

Research priorities

Large randomized controlled trials of airway clearance techniques in bronchiectasis would be desirable, but present complex challenges due to airway clearance being standard of care. Key research priorities in this area include

What the impact of airway clearance techniques on exacerbations over the long term(e.g 12 months or greater)

- What is the optimal method of delivery of airway clearance technique training

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- Are virtual methods such as online training or video/remote training effective for delivery of airway clearance techniques

– What is the added benefit of airway clearance devices?

- Is exercise as effective as airway clearance techniques in improving respiratory symptoms and should patients performing regular exercise also use airway clearance techniques regularly?58

- What is the effectiveness and optimal application of ACTs during acute exacerbations, and how should these techniques be adapted based on exacerbation severity and individual patient characteristics?

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PICO QUESTION 2

|Should mucoactive drugs be used(compared with no mucoactive drugs) in adults with bronchiectasis?|||| |---|---|---|---| |POPULATION:|Adults with bronchiectasis||| |INTERVENTION:|Mucoactive drugs|Mucoactive drugs|| |COMPARISON:|No mucoactive drugs|No mucoactive drugs|| |MAIN OUTCOMES:|Exacerbations (critical)||| |MAIN OUTCOMES:|Quality of Life (critical)||| |MAIN OUTCOMES:|Symptoms measured using symptom questionnaires or other validated methods (important)||| |MAIN OUTCOMES:|Adverse events (critical)||| |MAIN OUTCOMES:|Severe exacerbations/ Hospitalisations (critical)||| |MAIN OUTCOMES:|Activities of daily living (critical)||| |MAIN OUTCOMES:|Patient satisfaction/ feedback (important)||| |MAIN OUTCOMES:|Sputum volume (important)||| |MAIN OUTCOMES:|SETTING:|OUTPATIENTS|OUTPATIENTS| |MAIN OUTCOMES:|PERSPECTIVE:|CLINICAL RECOMMENDATIONS FOR INDIVIDUAL PATIENTS|| |MAIN OUTCOMES:|PERSPECTIVE:|Inhaled mucoactive treatments(e.g hypertonic saline) and oral mucoactive treatments (N-acetylcysteine and Carbocisteine) are used to manage symptoms in European practice.|| |MAIN OUTCOMES:|CONFFLICT OF INTERESTS:|None reported||

ASSESSMENT

|Problem Is the problem a priority?|||| |---|---|---|---| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS|| |o No o Probably no O Probably yes X Yes o Varies o Don't know|Respiratory symptoms(such as cough and sputum production) are the most common in patients with bronchiectasis and impair quality of life and social interactions and are therefore of high importance||| |Desirable Effects How substantial are the desirable anticipated effects?|||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS|| |o Trivial o Small X Moderate o Large o Varies o Don't know|The pooled data shows statistically significant improvements in quality of life and symptoms which are clinically meaningful. However, the evidence regarding exacerbations shows variability across studies|Exacerbation data for two studies was not reported in a format which could be pooled.|| |Desirable Effects How substantial are the desirable anticipated effects?|||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS|| |o Trivial o Small X Moderate o Large o Varies o Don't know||Exacerbation data for two studies was not reported in a format which could be pooled.|| |Downloaded from https://publications.ersnet.org on September 29, 2025 by guest. Please see licensing information on first page for reuse rights.||||

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|Undesirable Effects How substantial are the undesirable anticipated effects?|||| |---|---|---|---| ||JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| ||o Large o Moderate X Small o Trivial o Varies o Don't know|There is evidence of adverse effects. There is an important trend to an increase in AEs overall, and the trial of DNAse shows worse exacerbation rate(incorporating non protocol defined events) and worse FEV1 at the end of treatment|Some trials exclude patients who have bronchospasm to the drug after a first test dose and so these data are not reflected in the reported AEs but would be important for application of these treatments in practice.| ||||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS|| |X Very low o Low o Moderate o High o No included studies|From GRADE assessment,,the certainty of evidence is very low.||| |Values is there important uncertainty about or variability in how much people value the main outcomes?|||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS|| |oImportant uncertainty or variability o Possibly important or variability or variability information,or Probably no important uncertainty X No important or variability|We did not specifically look for studies assessing patient values|Patients and clinicians in the TF fully agreed that exacerbations, quality of life and symptoms are key outcomes|| |JUDGEMENT|RESEARCH EVIDENCE|||

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|European Respiratory Journal Page 128 of 177|||| |---|---|---|---| |o Favors the comparison o Probably favors the comparison favor either the intervention or the comparison X Probably favors the intervention o Varies o Don't know|There is clear evidence of benefit but there are also important safety signals. The balance would suggest a beneficial effect driven by trials of hypertonic saline, mannitol and N-acetylycysteine. DNAse showed no evidence of effectiveness and potential harm.||| |Resources required How large are the resource requirements(costs)?|||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS|| |O Large costs o Moderate costs o Negligible costs and savings o Moderate savings o Large savings oVaries X Don't know|We did not look for studies on resources required|It is known that nebulized mucoactive treatments require not only the drug but also provision of nebulizer devices.|| ||||| |Certainty of evidence of required resources What is the certainty of the evidence of resource requirements(costs)?|||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS|| |o Very low o Low o Moderate o High X No included studies|We did not look for studies on resources required||| ||||| |Cost effectiveness|Cost effectiveness|Cost effectiveness|| |Does the cost-effectiveness of the intervention favor the intervention or the comparison?|||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS||

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|o Favors the comparison o Probably favors the favors the comparison o Does not favor either the intervention or the comparison o Probably favors the intervention o Favors the intervention o Varies X No included studies|We did not look for studies studies examining cost effectiveness|||||| |---|---|---|---|---|---|---| |Equity What would be the impact on health equity?|ADDITIONAL CONSIDERATIONS|||||| |JUDGEMENT|JUDGEMENT|RESEARCH EVIDENCE|RESEARCH EVIDENCE|We are not aware of any impact on health equity. The included studies did not assess this||| |o Reduced o Probably reduced o Probably no impact o Probably o Increased o Varies increased X Don't know||||||| |Acceptability Is the intervention acceptable to key stakeholders?||||||| |JUDGEMENT|RESEARCH EVIDENCE|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS|:||| |o No o Probably no yes X Yes o Varies no predict o Probably know||||||| |Feasibility Is the intervention feasible to implement?|Registry data suggests mucoactive drugs are widely used. Patient members of the panel commented that mucoactive drugs are acceptable, with a preference for a lower treatment burden (e.g oral rather than inhaled where possible)|||||| |Feasibility Is the intervention feasible to implement?||||||| |JUDGEMENT|RESEARCH EVIDENCE|RESEARCH EVIDENCE|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS||| |o No o Probably no Yes X Yes o Varies o Don't know||||Oral mucoactive drugs may be easier to introduce than||| |Feasibility Is the intervention feasible to implement?||||||| |JUDGEMENT|RESEARCH EVIDENCE|RESEARCH EVIDENCE|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS||| |o No o Probably no|We did not search for studies assessing feasibility|Oral mucoactive drugs may be easier to introduce than|||||

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|o Probably yes||| |---|---|---| |X Yes||| |o Varies o Don't know|||

SUMMARY OF JUDGEMENTS

||JUDGEMENT|JUDGEMENT|JUDGEMENT|JUDGEMENT|JUDGEMENT|JUDGEMENT|JUDGEMENT| |---|---|---|---|---|---|---|---| ||PROBLEM|No|Probably no|Probably yes|Yes||Varies| |DESIRABLE EFFECTS|Trivial|Small|Moderate|Large||Varies|Don't know| |UNDESIRABLE EFFECTS|Large|Moderate|Small|Trivial||Varies|Don't know| |CERTAINTY OF EVIDENCE|Very low|Low|Moderate|High|||No included studies| |VALUES|Important uncertainty or variability|Possibly important uncertainty or variability|Probably no important uncertainty or variability|No important uncertainty or variability|||| |BALANCE OF EFFECTS|Favors the comparison|Probably favors the comparison|Does not favor either the intervention or the comparison|Probably favors the intervention|Favors the intervention|Varies|Don't know| |RESOURCES REQUIRED|Large costs|Moderate costs|Negligible costs and savings|Moderate savings|Large savings|Varies|Don't know| |CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES|Very low|Low|Moderate|High|||No included studies| |Cost effectiveness|Favors the comparison|Probably favors the comparison|Does not favor either the intervention or the comparison|Probably favors the intervention|Favors the intervention|Varies|No included studies| |EQUITY|Reduced|Probably reduced|Probably no impact|Probably increased|Increased|Varies|Don't know| |ACCEPTABILITY|No|Probably no|Probably yes|Yes||Varies|Don't know| |FEASIBILITY|No|Probably no|Probably yes|Yes||Varies|Don't know|

TYPE OF RECOMMENDATION- MUCOACTIVE DRUGS

|Strong recommendation against the intervention|Conditional recommendation against the intervention|Conditional recommendation for either the intervention or the comparison|Conditional recommendation for either the intervention or the comparison|Strong recommendation for the intervention| |---|---|---|---|---| |O|O|O|X|O|

TYPE OF RECOMMENDATION- RECOMBINANT DNASE

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|Strong recommendation against the intervention|European Respiratory Journal||||| |---|---|---|---|---|---| |2|Strong recommendation against the intervention|Conditional recommendation for otherwise the intervention or the comparison|Conditional recommendation for conditional recommendation for either the intervention or the intervention||| |2|||O|O|| |6|||||| |7|||||| |8|||||| |9|||||| |10|||||| |11|||||| |12|||||| |13|||||| |14|||||| |15|||||| |16|||||| |17|||||| |18|||||| |19|||||| |16|||||| |17|||||| |18|||||| |19|||||| |20|||||| |21|||||| |22|||||| |23|||||| |24|||||| |25|||||| |26|||||| |27|||||| |28|||||| |29|||||| |27|||||| |28|||||| |29|||||| |30|||||| |31|||||| |32|||||| |33|||||| |34|||||| |35|||||| |36|||||| |37|||||| |38|||||| |38|||||| |38|||||| |38|||||| |40|||||| |41|||||| |42|||||| |43|||||| |44|||||| |45|||||| |46|||||| |27|||||| |46|||||| |47|||||| |28|||||| |48|||||| |30|||||| |31|||||| |32|||||| |33|||||| |34|||||| |35|||||| |37|||||| |38|||||| |39|||||| ||||||| |Subgroup considerations|||||| ||||||| ||||||| |Subgroup considerations|||||| ||||||| ||||||| ||||||| ||||||| ||||||| ||||||| ||||||| ||||||| ||||||| ||||||| ||||||| ||||||| ||||||| ||||||| |||</ </|</ </|||

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Research priorities

Large randomized controlled trials utilizing precision medicine approaches, which tailor mucoactive treatments towards individual patients with high symptom burden and/or particular sputum characteristics (i.e abnormal mucins, mucus properties or DNA content), are needed as moderately sized trials show inconsistent results. Recombinant human DNase proved ineffective in a trial published in 1998. However, given the strong link between neutrophil extracellular traps and poor disease outcomes, and increasing recognition of bronchiectasis endotypes, further research is warranted in order to clarify whether specific subgroups of adults with 1998.

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PICO QUESTION 3

Should long term inhaled antibiotics be used(compared with no long term inhaled antibiotics) in adults with bronchiectasis?

|POPULATION:|Adults with bronchiectasis| |---|---| |POPULATION:|Long term inhaled antibiotics| |COMPARISON:|No Long term inhaled antibiotics| |MAIN OUTCOMES:|Exacerbations (critical)| |MAIN OUTCOMES:|Severe exacerbations(critical)| |QUALity of life(critical)|| |QUALity of life(critical)|Adverse events(critical)| |New isolation of pathogens(critical)|| |New isolation of pathogens(critical)|Mortality(critical)| |Mortalityity(critical)|| |Mortalityity(critical)|Antibiotic resistance(important)| |$$\begin{array}{l}\text{ SETTING:}\\ \\ \\ \\ \\ \end{array}$$|OUTPATIENT| |PERSPECTIVE:|CLINICAL RECOMMENDATIONS FOR INDIVIDUAL PATIENTS| |PERSPECTIVE:|Inhaled antibiotics are used to prevent exacerbations in patients with chronic airway infection, predominantly P. aeruginosa| |CONFLICT OF INTERESTS:|10 panel members declared relevant COls and did not vote on this question.|

ASSESSMENT

|Problem Is the problem a priority?||| |---|---|---| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| |o No o Probably no Yes X Yes o Varies o Don't know|Inhaled antibiotics are widely used, and reducing exacerbations is a major clinical priority for people with bronchiectasis.|| |||| |Desirable Effects How substantial are the desirable anticipated effects?||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| |o Trivial o Small X Moderate o Large Notably o Varies o Don't know|Clinically relevant reductions in exacerbations have been reported and demonstrated in our meta-analysis. All of the exacerbations are consistent with benefit. There is no consistent improvement in symptoms demonstrated. The benefit on exacerbations is primarily derived from studies of patients infected with Pseudomonas aeruginosa. Notably the PROMIS, ORBIT, IBEST and so single centre studies enrolled exclusively. P aeruginosa positive patients. Some benefit was demonstrated in the RESPIRE trials, but not in the AIR-BX studies. These latter two programmes included patients with P. aeruginosa and patients without P. aeruginosa.|The effect on severe exacerbations is larger than for moderate exacerbations. Severe exacerbations are clinically relevant.| |Undesirable Effects|Undesirable Effects|Undesirable Effects|

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|How substantial are the undesirable anticipated effects?||| |---|---|---| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| |o Large o Moderate X Small o Trivial o Varies o Don't know|There is no significant increase in the risk of overall adverse events between the groups and no difference in the risk of all cause mortality. The 95% Cl includes an upper limit of 46 more adverse events per 1000 patients treated. The data therefore suggests a profile very similar to placebo. There is a significant increase in resistance with inhaled antibiotics.|Some studies report an increase in adverse effects including bronchospasm, particularly in studies of aminoglycosides.| |Certainty of evidence What is the overall certainty of the evidence of effects?||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| |o Very low oLow X Moderate o High o No included studies|Based on GRADE assessment.|The majority of evidence comes from studies of patients infected with P. aeruginosa and so the certainty of evidence is lower in patients without P. aeruginosa infection.| |Values Is there important uncertainty about or variability in how much people value the main outcomes?||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| |oImportant uncertainty or variability o Possibly important o Probably or variability no important uncertainty X No important or variability uncertainty or variability|We did not search for studies assessing patient values|All outcomes were rated as critical or important with consistent rating among the clinical and patient reviewers for the majority of clinically relevant outcomes with the exception of resistance. There is no agreement within the community about the clinical relevance and interpretation of antibiotic resistance and so this was rated important by some members of the panel and not important by others.| |Balance of effects Does the balance between desirable and undesirable effects favor the intervention or the comparison?||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS|

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|o Favors the comparison antibiotics. This is especially the case for severe exacerbations which are clinically important.The balance of risk and benefits is favourable.There is no significant increase in the risk of adverse events.|As there are several potentially effective treatments the position of inhaled antibiotics relative to other treatments in view of the treatment burden must be considered.|||| |---|---|---|---|---| |Resources required How large are the resource requirements(costs)?||||| |JUDGEMENT|JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS|| |o Large costs o Moderate costs o Negligible costs and savings o Moderate|We did not search for studies assessing resources|Inhaled antibiotics are not inexpensive and require services to deliver as well as nebulizer devices. Therefore there are resource implications for their use and administration.Sometimes caregivers need to be involved in preparing medication or administering which is not the case for oral medications in many cases. Challenge testing is performed in many countries/healthcare settings which requires organizational resources. Compared to other other environments and||| |Certainty of evidence of required resources||||| |What is the certainty of the evidence of resource requirements(costs)?||||| |JUDGEMENT|JUDGEMENT|RESEARCH EVIDENCE||| |Certainty of evidence of required resources What is the certainty of the evidence of resource requirements(costs)?|||||

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||o Very low o Low o Moderate o High X No included studies|There are no formal assessments of the costs involved|| |---|---|---|---| ||o Very low o Low o Moderate o High X No included studies|There are no formal assessments of the costs involved|| |Cost effectiveness|Cost effectiveness|Cost effectiveness|| |JUDGEMENT|RESEARCH EVIDENCE||ADDITIONAL CONSIDERATIONS| |o Favors the comparison o Probably favors the comparison favor either the intervention or the comparison|We did not search for cost-effectiveness stuides||The cost effectiveness likely depends on the patient population in which they are used.The large reduction in severe exacerbations means large cost savings may be possible if used in patients at high risk of severe exacerbations| |or the comparison X Probably favors the intervention o Varies X No included studies|||| |Equity What would be the impact on health equity?|||| |JUDGEMENT|RESEARCH EVIDENCE||ADDITIONAL CONSIDERATIONS| |o Reduced o Probably reduced no impact o Probably increased o Varies X Don't know|We did not look for evidence with regard to health equity.||Inhaled antibiotics are not available in all countries and nebulizer device access also varies. Therefore access to these medications may be limited to high income countries or countries with health systems where the treatments are reimbursed Registry data shows use of inhaled antibiotics are currently limited to specific countries and particularly high income countries.|

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|||||||||| |---|---|---|---|---|---|---|---|---| |Acceptability Is the intervention acceptable to key stakeholders?||||||||| |JUDGEMENT|RESEARCH EVIDENCE||||ADDITIONAL CONSIDERATIONS|||| |o No o Probably no O Probably yes o Yes o Varies X Don't know|We did not look for studies on acceptability.||||Inhaled antibiotics are used by approx. 7% of patients with bronchiectasis in Europe according to the EMBARC registry. Adherence data suggests that many patients do not continue to use inhaled antibiotics (approx. 50% in some studies). Drop out rates in randomized trials are often around 30%. Treatment burden is an important consideration for patients|||| |Feasibility Is the intervention feasible to implement?||||||||| |JUDGEMENT|RESEARCH EVIDENCE||||ADDITIONAL CONSIDERATIONS|||| |o No o Probably no O Probably yes o Varies X Don't know|Studies identified no significant issues with feasibility but we did not specifically look for feasibility studies.||||Inhaled antibiotic administration feasibility depends a lot on healthcare system, including the availability of nebulizers, reimbursement of availability of services to deliver the treatments including test doses.There are regulatory issues. Therefore feasibility varies and this is reflected in large differences between countries in the use of these medications.|||| |||||||||| |SUMMARY OF JUDGEMENTS||||||||| |||||||||| |PROBLEM|No|Probably no|Probably yes|Yes|Varies|Don't know||| |DESIRABLE EFFECTS|Trivial|Small|Moderate|Large|Varies|Don't know||| |UNDESIRABLE EFFECTS|Large|Moderate|Small|Trivial|Varies|Don't know||| |CERTAINTY OF EVIDENCE|Very low|Low|Moderate|High||No included studies||| |VALUES|Important uncertainty or variability|Possibly important uncertainty or variability|Probably no important uncertainty or variability|No important uncertainty or variability||||| |BALANCE OF EFFECTS|Favors the comparison|Probably favors the comparison|Does not favor either the|Probably favors the intervention|Varies|Don't know|||

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Justification

A strong recommendation was made for patients chronically infected with P. aeruginosa, based on clinically relevant reduction in exacerbation frequency, including severe exacerbations. A conditional recommendation was made for patients with other chronic infections, given the predominance of P. aeruginosa in the available meta-analysis and the availability of effective treatments, including long term macrolides, in these patients. The recommendation prioritises the clinically relevant improvements in exacerbation outcomes, in the context of the poor outcomes experienced by patients with chronic P. aeruginosa infection, and is also informed by the lack of any significant increase in adverse events. The panel acknowledged the risk of antimicrobial resistance which is important at population level but is of uncertain significance for the individual patient in the context of inhaled antibiotics. Feedback from patients also supported a strong recommendation.

Previous guidelines recommended the use of long-term treatments such as inhaled antibiotics for patients with 3 or more exacerbations per year. The current wording of the recommendation reflects the understanding that the number of exacerbations in the previous year is an important risk factor for future exacerbations but is not the only risk factor. Patients with a high burden of daily symptoms are also at high risk of future exacerbations, and the threshold to commence long-term treatments may be lower in patients with other important prognostic features. Clinical features associated with a higher risk of future exacerbations include P.aeruginosa infection, PCD, COPD, RA and sputum purulence.The present recommendation, therefore, suggests that patients with 2 or more exacerbations are likely to be at high risk of future exacerbations, but that some patients with a lower number of exacerbations with a high symptom burden may also benefit from preventative treatment.The threshold to commence treatment should be individualised taking into account the key risk factors in each individual patient as well as considerations around the balance of risks and benefits, availability, cost and the burden of treatment.

Antimicrobial stewardship is a key consideration. Long-term antibiotic treatment should be used after other aspects of treatment have been optimised and, therefore,other options such as airway clearance, vaccination against respiratory pathogens, treatment of underlying causes and co-morbidities have been addressed.

Subgroup considerations

P. aeruginosa and non-P. aeruginosa infected patients as described above.

Implementation considerations

Inhalation of antibiotics requires not just an appropriate medication but also access to and supply of an appropriate nebulizer.

Monitoring and evaluation

Treatment should be prescribed for a defined period and reevaluated. If there is no evidence of efficacy then inhaled antibiotics should be discontinued and other therapies considered to reduce exacerbations.

Research priorities

Although inhaled antibiotics show efficacy in studies, predicting individual response remains a challenge as reflected by inconsistent results across RCTs. The panel,therefore, recommends studies that should focus on precision approaches to optimize treatment selection. Key research questions include: i) Can inflammatory or microbial biomarkers predict patients' response to inhaled antibiotics?; ii) What is the best way of identifying patients at risk of future exacerbations? ii) What is the impact of inhaled antibiotics on antimicrobial resistance and what, if any,are the clinical consequences of resistance on treatment efficacy and future outcomes.

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PICO QUESTION 4

|Should long-term macrolides be used(compared with no long-term macrolides) in adults with bronchiectasis?|||| |---|---|---|---| |POPULATION:|Adults with bronchiectasis||| |INTERVENTION:|Long term macrolide treatment||| |COMPARISON:|No Long term macrolide treatment||| |MAIN OUTCOMES:|Exacerbations(critical)||| ||Quality of life(critical)||| ||Adverse events(critical)||| ||New isolation of pathogens(important)||| ||Mortality(critical)||| ||Antibiotic resistance(important)||| ||Hospitalisation(critical)||| |SETTING:|OUTPATIENT||| |PERSPECTIVE:|CLINICAL RECOMMENDATIONS FOR INDIVIDUAL PATIENTS||| |BACKGROUND:|Macrolides are used as a prophylactic treatment to prevent exacerbations. Current usage is just under 20% of all patients with bronchiectasis in Europe according to the EMBARC registry||| |CONFLICT OF INTERESTS:|None declared.|||

ASSESSMENT

|Problem Is the problem a priority?|||| |---|---|---|---| |JUDGEMENT|RESEARCH EVIDENCE||ADDITIONAL CONSIDERATIONS| |o No o Probably no o Probably yes X Yes o Varies o Don't know|Macrolides are widely used, and reducing exacerbations is a major clinical priority for people with bronchiectasis||Patients believe that long term treatments to prevent exacerbations and prevent deterioration are a priority.| |Desirable Effects How substantial are the desirable anticipated effects?|||| |JUDGEMENT|RESEARCH EVIDENCE||ADDITIONAL CONSIDERATIONS| |o Trivial o Small|Large highly clinically relevant reductions in exacerbations, estimated as a 52% reduction in exacerbations, have been reported and demonstrated in our meta-analysis. There is also a significant improvement in quality of life as measured by the st Georges respiratory questionnaire.||Lack of available data on severe exacerbations| |X Large|Benefits are consistent across multiple subgroups including patients with frequent (>2) and less frequent exacerbations, and patients with P.aeruginosa infection who are not conventionally treated with macrolides for||Sample size overall of studies is low(371 patients for exacerbation frequency for example)| ||||| ||||nevertheless the studies show very strong beneficial effects.|

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|Undesirable Effects How substantial are the undesirable anticipated effects?|||| |---|---|---|---| ||JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| ||o Large o Moderate X Small o Trivial o Varies o Don't know|While some studies show an increase in adverse events(notably the BAT trial) the overall adverse event profile shows no significant increase in adverse events.The confidence intervals are wide and include the possibility of an increase in antimicrobial resistance, isolation of new pathogens and to a lesser extent adverse events. There was very little data on mortality.|Macrolides are known to have adverse effects related to Gastrointestinal side effects and antimicrobial resistance in some cases.| ||Certainty of evidence||| ||What is the overall certainty of the evidence of effects?||| ||JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| ||o Very low o Low X Moderate o High No included studies|Based on GRADE assessment.|| |Values Is there important uncertainty about or variability in how much people value the main outcomes?|||| ||JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| ||oImportant uncertainty or variability of the|We did not search for studies assessing patient values|All outcomes were rated as critical or important with consistent rating among the clinical and patient reviewers| ||variability or Probably o Probably o Probably no important uncertainty or X No important uncertainty or variability||Patient members of the panel confirmed that the outcomes used were of high clinical importance to them.| |Balance of effects Does the balance between desirable and undesirable effects favor the intervention or the comparison?|||| ||JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS|

|European Respiratory Journal|||| |---|---|---|---| |o Favors the|o Favors the|o Favors the|| |comparison|comparison|comparison|| |o Probably favors the|||| |comparison|comparison|comparison|| |o Probably favors the|||| |either the intervention or|||| |the comparison|the comparison|the comparison|| |o Probably favors the intervention|||| |o Varies o Don't know|||| |Resources required|Resources required|Resources required|Resources required| |How large are the resource requirements (costs)?|||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS|| |o Large costs X Moderate costs costs|We did not specifically look for studies assessing required resources.|Macrolides are inexpensive, but monitoring recommended by some guidelines (ECG,NTM culture, hearing examination etc) has a degree of cost and resource (staff time) associated with it.|| |o Moderate savings oVaries o Don't know|||| |Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)?|||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS|| |o Very low|We did not specifically look for studies on resources required. We base our judgment on required resources on clinical experience|ADDITIONAL CONSIDERATIONS|| |XLow|||| |o Moderate|||| |o High|||| |o No included studies|||| ||||| |Cost effectiveness|Cost effectiveness|Cost effectiveness|| |Does the cost-effectiveness of the intervention favor the intervention or the comparison?|||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS||

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|o Favors the comparison o Probably favors the comparison otherwise either the intervention or the comparison favors the intervention o Probably favors the intervention o Favors the intervention o Varies o No included studies|We did not specifically seek cost effectiveness studies.|There are no cost effectiveness studies that were identified by our search but it is highly likely the intervention is cost effective in view of the magnitude of benefit.|||| |---|---|---|---|---|---| |Equity What would be the impact on health equity?|||||| |JUDGEMENT||RESEARCH EVIDENCE||ADDITIONAL CONSIDERATIONS|| ||o Reduced o Probably reduced o Probably no impact o Probably increased X Increased||We did not search for studies assessing health equity||Macrolides are widely available and cheap and therefore support health equity as they can be easily deployed in resource poor settings.| |27|||||Macrolides are more feasible to prescribe than some alternative treatments such as inhaled antibiotics which may favour health equity.| ||||||| |Acceptability Is the intervention acceptable to key stakeholders?|||||| ||JUDGEMENT||RESEARCH EVIDENCE||ADDITIONAL CONSIDERATIONS| ||o No o Probably no O Probably yes X Yes o Varies o Don't know||||Macrolides are widely used by clinicians and patients and are well accepted.| |Feasibility Is the intervention feasible to implement?|||||| ||JUDGEMENT||RESEARCH EVIDENCE||ADDITIONAL CONSIDERATIONS| ||o No o Probably no O Probably yes X Yes o Varies o Don't know||||Macrolides are widely used by clinicians and patients and are well accepted.| |Feasibility Is the intervention feasible to implement?|||||| ||JUDGEMENT||RESEARCH EVIDENCE||ADDITIONAL CONSIDERATIONS| ||o No o Probably no O Probably yes X Yes o Varies o Don't know||||Macrolides are widely used by clinicians and patients and are therefore feasible to use in practice.|

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1 2 3 4 5 6 7 8 9 10 11 12 14 15 16 17 18 90 10 11 12 13 14 15 16 17 18 99 37 38 41 42 43 45 46 47 49 48 51 53 54 55 57 58 60

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SUMMARY OF JUDGEMENTS

||JUDGEMENT|JUDGEMENT|JUDGEMENT|JUDGEMENT|JUDGEMENT|JUDGEMENT|| |---|---|---|---|---|---|---|---| ||PROBLEM|No|Probably no|Probably yes|Yes||Varies| |$$\text{ESIRABLE EFFECTS}$$|Trivial|Small|Moderate|Large||Varies|Don't know| |UNDESIRABLE EFFECTS|Large|Moderate|Small|Trivial||Varies|Don't know| |CERTAINTY OF EVIDENCE|Very low|Low|Moderate|High|||No included studies| |VALUES|Important uncertainty or variability|Possibly important uncertainty or variability|Probably no important uncertainty or variability|No important uncertainty or variability|||| |BALANCE OF EFFECTS|Favors the comparison|Probably favors the comparison|Does not favor either the intervention or the comparison|Probably favors the intervention|Favors the intervention|Varies|Don't know| |RESOURCES REQUIRED|Large costs|Moderate costs|Negligible costs and savings|Moderate savings|Large savings|Varies|Don't know| |CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES|Very low|Low|Moderate|High|||No included studies| |Cost effectiveness|Favors the comparison|Probably favors the comparison|Does not favor either the intervention or the comparison|Probably favors the intervention|Favors the intervention|Varies|No included studies| |EQUITY|Reduced|Probably reduced|Probably no impact|Probably increased|Increased|Varies|Don't know| |ACCEPTABILITY|No|Probably no|Probably yes|Yes||Varies|Don't know| |FEASIBILITY|No|Probably no|Probably yes|Yes||Varies|Don't know|

TYPE OF RECOMMENDATION

|Strong recommendation against the intervention|Conditional recommendation against the intervention|Conditional recommendation for either the intervention or the comparison O|Conditional recommendation for the intervention for the intervention| |---|---|---|---| ||||$\sigma$|

CONCLUSIONS

Recommendation

Recommendation

We recommend to offer long-term macrolides to patients at high risk of exacerbations despite standard care(Strong recommendation for the intervention, moderate certainty of evidence)

Remarks

●Macrolides are effective in a broad group of patients with bronchiectasis at high risk of exacerbations including patients with chronic P. aeruginosa infection, patients with airway infection caused by other pathogens, and those without evidence of airway infection.

●Macrolides should not be prescribed as monotherapy to patients with NTM infection. NTM infection should be excluded before initiating macrolide therapy.

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The most widely used long-term macrolide is azithromycin, typically at a dose of 250 mg daily or three times per week, or 500 mg three times per week.

In view of the risk of adverse effects, patient education, baseline screening, and appropriate follow-up are important when prescribing macrolides.

Justification

A strong recommendation is supported by a highly clinically relevant reduction in exacerbations and a highly meaningful improvement in quality of life with long-term macrolide treatment. The trials show no major safety concerns, and in studies of 6 to 12 months duration, antimicrobial resistance was not identified as a significant issue.The largest studies included patients with at least 1 exacerbation per year, and benefit was demonstrated across multiple patient subgroups including those with low exacerbation frequency and the subgroup of patients with P. aeruginosa infection.

While previous guidelines recommended the use of long-term treatments such as macrolides for patients with 3 or more exacerbations per year, the current wording of the recommendation reflects the recognition that past exacerbation frequency is a key, but not exclusive, predictor of future risk. Patients with a high burden of daily symptoms are also at high risk of future exacerbations, and, in such cases, the threshold for initiating long-term treatments may be lower. Clinical features associated with a higher risk of future exacerbations include P. aeruginosa infection, PCD, COPD, RA and sputum purulence. The present recommendation therefore suggests that patients with>=2 exacerbations are likely to be at high risk of future exacerbations, but that some patients with a lower number of exacerbations with a high symptom burden or other risk factors may also benefit from preventative treatment. The threshold to commence treatment should be individualised, based on patient-specific risk factors, risk-benefit balance, and treatment burden.

Subgroup considerations

A meta-analysis of RCTs shows a highly significant reduction in exacerbations in the severe subgroup infected with P. aeruginosa infection. While based on a small sample size(61 patients), the results are convincing and support the use of macrolides in this patient population. Time to first exacerbation, SGRQ and lung function changes are also consistently as least as good in the P. aeruginosa subpopulation compared to the non-Pseudomonas subpopulation.

Implementation considerations

Appropriate monitoring before and after prescription of macrolide is important, including testing for LFTs, ECG(QT interval) and NTM culture prior to treatment.

Adverse effects appear larger in studies that use higher doses and so clinicians may wish to commence patients on the lowest effective dose(250mg or 500mg three times per week)

Monitoring and evaluation

Patients should be monitored, for example refer to BTS macrolide guidance. Patients receiving macrolide maintenance therapy should be monitored at least yearly for efficacy(no.of exacerbations, symptoms) and side effects). The optimal duration of treatment with macrolides is not known and the longest studies are up to 12 months. Consider the withdrawal of macrolide treatment after one year if there is no obvious efficacy or alternatively if remission of exacerbations and symptoms is reached. In the latter case, a careful discussion about the risks and benefits of withdrawal is needed due to the risk of relapse.

Research priorities

What is the long term safety of macrolides in terms of antimicrobial resistance, emergent pathogens and adverse effects beyond 12 months

Can macrolide treatment at an early stage of disease(e.g mild bronchiectasis with infrequent exacerbations but risk factors for progression) result in slowing progression of disease or achieve remission?

What the optimal monitoring strategy for adverse events of macrolides? Do all patients require ECG pre and post macrolide treatment? Is NTM screening required for all patients or only patients with high risk clinical features? What is the value of audiology screening before or after macrolide treatment?

In patients who are clinically stable with a low symptom/exacerbation burden can macrolides be safely discontinued?

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PICO QUESTION 5

|Should long-term non-macrolide oral antibiotics be used(compared to no long-term non-macrolide oral antibiotics)||| |---|---|---| |in adults with bronchiectasis?||| |POPULATION:|Adult patients with bronchiectasis|| |INTERVENTION:|Long-term non-macrolide oral antibiotics|| |COMPARISON:|No long term non macrolide oral antibiotics|| |MAIN OUTCOMES:|Exacerbations(critical) Quality of life(critical) Mortality(critical) Adverse events(critical) Symptoms measured using symptom questionnaires or other validated methods(important) Severe exacerbations(critical) Antibiotic resistance(important) Occurrence of new potential pathogenic microorganisms(important)|| |SETTING:|OUTPATIENTS|OUTPATIENTS| |PERSPECTIVE:|CLINICAL RECOMMENDATIONS FOR INDIVIDUAL PATIENTS|| |BACKGROUND:|Long term non-macrolide oral antibiotics are a potential prophylactic treatment to prevent exacerbations that have been widely used in some regions in the past and continue to be used in some patients.|| |CONFLICT OF INTERESTS:|None reported|None reported|

ASSESSMENT

|Problem Is the problem a priority?|||| |---|---|---|---| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS|| |o No o Probably no o Probably yes X Yes o Varies o Don't know|Although macrolides provide an excellent evidence based treatment for adult patients with frequent exacerbations, there is a real concern of pathogen resistance, certainly in regions where non-tuberculous mycobacteria are frequently present in these patients. Also, cardiovascular and gastro-intestinal side-effects of macrolide necessitate the need for alternatives.||| |Desirable Effects How substantial are the desirable anticipated effects?|||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS|| |X Trivial o Small o Moderate o Large o Varies o Don't know|The analysis shows no clinically meaningful benefit in any of the outcomes. Some reduction can be seen for shortness of breath and sputum volume outcomes, however these reductions were limited.|||

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|Undesirable Effects How substantial are the undesirable anticipated effects?||| |---|---|---| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| |o Large o Moderate X Small o Trivial o Varies o Don't know|The analysis shows only a small increase in number of adverse events in the treatment arm. There was also a small increase in new potential pathogenic organisms in the treatment arm as well as a small increase in antibiotic resistance. However, no statistical analysis was possible.|Oral antibiotics are known to carry a risk of increasing antimicrobial resistance and common side effects are known to include gastrointestinal side effects. Long term risks in relation to antimicrobial resistance are unknown.| |Certainty of evidence What is the overall certainty of the evidence of effects?||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| |X Very low oLow o Moderate o High o No included studies|The certainty of evidence is very low, based on GRADE assessment.|| |Values Is there important uncertainty about or variability in how much people value the main outcomes?||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| |oImportant uncertainty or variability o Possibly important uncertainty or variability|We did not search for studies assessing patient values|The endpoints such as exacerbations, symptoms and antibiotic resistance were all considered important by the patient representatives of the panel| |Balance of effects Does the balance between desirable and undesirable effects favor the intervention or the comparison?||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS|

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|European Respiratory Journal Page 148 of 177||| |---|---|---| |XFavors the comparison oProbably favors the comparison o Does not favor either the intervention or the comparison o Probably favors the intervention o Favors the intervention o Varies o Don't know|The limited positive effects of the interventions and the small increase in undesirable effects does not support the use of the intervention.|The availability of better alternative treatments such as long term macrolides and inhaled antibiotics also impacts on this consideration.| |Resources required How large are the resource requirements (costs)?||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| |o Large costs o Moderate costs o Moderate costs and savings oModerate savings oLarge savings oVaries X Don't know|We did not look for studies on resource requirements|Penicillin, oxytetracycline and amoxicillin are inexpensive and widely available and therefore resource requirements are low.None of these treatments are currently widely used as long-term non-macrolide treatment,therefore no significant savings can be suspected either.| |Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)?||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| |o Very low o Low o Moderate o High X No included studies|We did not look for studies on resource requirements|| |Cost effectiveness Does the cost-effectiveness of the intervention favor the intervention or the comparison?||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS|

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|oFavors the comparison oProbably favors the comparison o Does not favor either the intervention or the comparison o Probably favors the intervention o Favors the intervention o Varies X No included studies|We did not look for studies on cost-effectiveness|| |---|---|---| |oFavors the comparison oProbably favors the comparison o Does not favor either the intervention or the comparison o Probably favors the intervention o Favors the intervention o Varies X No included studies||| |Equity What would be the impact on health equity?||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| |o Reduced o Probably reduced o Probably no impact o Probably increased o Varies X Don't know|We did not look for studies on health equity|A cheap and widely available therapy that can be implemented in low resource settings could have a positive effect on health equity.| |Acceptability Is the intervention acceptable to key stakeholders?||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| |o No o Probably no o Probably yes o Yes o Varies X Don't know|We did not look for studies assessing acceptability|The treatment is widely used and is acceptable to patients and clinicians.| |Feasibility Is the intervention feasible to implement?||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| |o No o Probably no o Varies x Don't know|We did not look for studies assessing feasibility|There are no implementation concerns as this therapy is widely used.|

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SUMMARY OF JUDGEMENTS

||JUDGEMENT|JUDGEMENT|JUDGEMENT|JUDGEMENT|JUDGEMENT|JUDGEMENT|JUDGEMENT| |---|---|---|---|---|---|---|---| ||No|Probably no|Probably yes|Yes||Varies|Don't know| |DESIRABLE EFFECTS|Trivial|Small|Moderate|Large||Varies|Don't know| |UNDESIRABLE EFFECTS|Large|Moderate|Small|Trivial||Varies|Don't know| |CERTAINTY OF EVIDENCE|Very low|Low|Moderate|High|||No included studies| |VALUES|Important uncertainty or variability|Possibly important uncertainty or variability|Probably no important uncertainty or variability|No important uncertainty or variability|||| |BALANCE OF EFFECTS|Favors the comparison|Probably favors the comparison|Does not favor either the intervention or the comparison|Probably favors the intervention|Favors the intervention|Varies|Don't know| |RESOURCES REQUIRED|Large costs|Moderate costs|Negligible costs and savings|Moderate savings|Large savings|Varies|Don't know| |CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES|Very low|Low|Moderate|High|||No included studies| |Cost effectiveness|Favors the comparison|Probably favors the comparison|Does not favor either the intervention or the comparison|Probably favors the intervention|Favors the intervention|Varies|No included studies| |EQUITY|Reduced|Probably reduced|Probably no impact|Probably increases|Increased|Varies|Don't know| |ACCEPTABILITY|No|Probably no|Probably yes|Yes||Varies|Don't know| |FEASIBILITY|No|Probably no|Probably yes|Yes||Varies|Don't know|

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TYPE OF RECOMMENDATION

|Strong recommendation against the intervention|Conditional recommendation against the intervention X|Conditional recommendation for either the intervention or the comparison|Conditional recommendation for the intervention|Strong recommendation for the intervention| |---|---|---|---|---|

CONCLUSIONS

Recommendation

Recommendation

The panel suggests NOT to offer long-term non-macrolide oral antibiotics as a first line treatment to adult patients with bronchiectasis and a high risk of exacerbations(conditional recommendation against the intervention, very low certainty of evidence).

Remarks

Long-term non-macrolide oral antibiotics may have a role in specific situations where patients are at high risk of frequent exacerbations and other options such as long-term macrolides are contraindicated or have proven ineffective.

Justification

The overall risk-benefit balance of long-term non-macrolide oral antibiotics appears to be unfavorable, given the lack of a clear reduction in exacerbations and other clinically relevant outcomes. The available studies are, however, hampered by small populations, unclear reporting of data, questionable inclusion criteria and sometimes a low number of events, resulting in very low certainty of evidence. Therefore, routine use of non-macrolide oral antibiotics is not recommended, as there is limited evidence, a risk of adverse effects and more effective first-line alternatives exist.

There are exceptional circumstances where non-macrolide maintenance antibiotics may be an appropriate treatment for bronchiectasis patients. This includes in patients at high risk of NTM or regions with high NTM prevalence16, or in patients unable to take macrolides due to adverse effects. Therefore, in cases where macrolides are contraindicated or ineffective, and there is clear evidence of infection in respiratory cultures, a trial of long-term, targeted non-macrolide antibiotic therapy may be justified.

Subgroup considerations

In patients where macrolides are contraindicated or have been ineffective and where other treatment options have been exhausted, a trial of long-term non-macrolide antibiotics might be considered.

Implementation considerations

Physicians and healthcare workers should be advised on the current lack of evidence supporting the use of non-macrolide long-term antibiotics in patients with bronchiectasis. Only in cases where macrolides are contra-indicated non-macrolides can be considered, but healthcare professionals should know that current data only show limited reduction in shortness of breath and sputum volume.

Monitoring and evaluation

As with all long term treatments a formal evaluation of efficacy is recommended if this treatment is used and the treatment should be stopped if ineffective.

Research priorities

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European Respiratory Journal

PICO QUESTION 7

|Should long-term inhaled corticosteroids be used(compared to no long-term inhaled corticosteroids) in adults with bronchiectasis?||| |---|---|---| |SETTING: PERSPECTIVE: BACKGROUND: PERSPECTIVE: CONFLICT OF INTERESTS:|Adults with bronchiectasis|| |SETTING: PERSPECTIVE: BACKGROUND: PERSPECTIVE: CONFLICT OF INTERESTS:|Long term Inhaled corticosteroids|| |SETTING: PERSPECTIVE: BACKGROUND: PERSPECTIVE: CONFLICT OF INTERESTS:|No long term inhaled corticosteroids|| |SETTING: PERSPECTIVE: BACKGROUND: PERSPECTIVE: CONFLICT OF INTERESTS:|Exacerbations (critical)|| |SETTING: PERSPECTIVE: BACKGROUND: PERSPECTIVE: CONFLICT OF INTERESTS:|Hospitalisation (critical)|| |SETTING: PERSPECTIVE: BACKGROUND: PERSPECTIVE: CONFLICT OF INTERESTS:|Quality of life (critical)|| |SETTING: PERSPECTIVE: BACKGROUND: PERSPECTIVE: CONFLICT OF INTERESTS:|Adverse events (critical)|| |SETTING: PERSPECTIVE: BACKGROUND: PERSPECTIVE: CONFLICT OF INTERESTS:|New isolation of non tuberculous mycobacteria (critical)|| |SETTING: PERSPECTIVE: BACKGROUND: PERSPECTIVE: CONFLICT OF INTERESTS:|FEV1 (important)|| |SETTING: PERSPECTIVE: BACKGROUND: PERSPECTIVE: CONFLICT OF INTERESTS:|Mortality (important)|| |SETTING: PERSPECTIVE: BACKGROUND: PERSPECTIVE: CONFLICT OF INTERESTS:|Sputum quantity (important)|| |SETTING: PERSPECTIVE: BACKGROUND: PERSPECTIVE: CONFLICT OF INTERESTS:|Pneumonia (important)|| |SETTING: PERSPECTIVE: BACKGROUND: PERSPECTIVE: CONFLICT OF INTERESTS:|OUTPATIENT|| |SETTING: PERSPECTIVE: BACKGROUND: PERSPECTIVE: CONFLICT OF INTERESTS:|CLINICAL RECOMMENDATIONS FOR INDIVIDUAL PATIENTS|| |SETTING: PERSPECTIVE: BACKGROUND: PERSPECTIVE: CONFLICT OF INTERESTS:|HALground: Inhaled corticosteroids are widely used in Europe as anti-inflammatory treatments with >50% of patients currently receiving them according to European registry data.|| |SETTING: PERSPECTIVE: BACKGROUND: PERSPECTIVE: CONFLICT OF INTERESTS:|CONFLICT OF INTERESTS:|None declared|

ASSESSMENT

|Problem|Problem| |---|---| |Is the problem a priority?|| |JUDGEMENT|RESEARCH EVIDENCE| |o No o Probably no oProbably yes X Yes o Varies o Don't know|Inhaled corticosteroids are widely used by approximately 50% of European patients with bronchiectasis according to EMBARC. Establishing their efficacy is important.| |Desirable Effects How substantial are the desirable anticipated effects?|| |JUDGEMENT|RESEARCH EVIDENCE|

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|European Respiratory Journal Page 154 of 177|||| |---|---|---|---| |x Trivial o Small The evidence from the meta-analysis do not identify any clinically meaningful effects of treatment including no significant effect on exacerbations, quality of life, symptoms or quality of life|||| |Undesirable Effects How substantial are the undesirable anticipated effects?|||| ||JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| ||o Large X Moderate|The trials demonstrate a significant increase in the frequency of adverse events in the treatment group compared to control/placebo group.These events are generally reported to be mild to moderate and include|There are well known adverse effects of inhaled corticosteroids in other diseases such as pneumonia, osteoporosis,| ||o Small|candidateis, sore throat and cough.Infections were reported. Important adverse events like pneumonia, risk|in other diseases such as pneumonia, osteoporosis,| ||o Varies oTrivial||diabetes, and local adverse effects such as candidiasis.| ||o Don't know||| |Values Is there important uncertainty about or variability in how much people value the main outcomes?|||| ||JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| ||JODGEMENT|RESEARCH EVIDENCE|Allutional consistent rating among its evidence is low.| ||o Very low X Low o Moderate o High o No included studies|According to GRADE rules the certainty of evidence is low.|The studies are small and so confidence in the reported effect estimates is low.There is a high risk of bias in the evidence presented. Studies include those which were open label, with selective reporting of outcomes and other important methodological limitations.| |Values Is there important uncertainty about or variability in how much people value the main outcomes?|||| ||JUDGEMENT|RESEARCH EVIDENCE|| ||o Important uncertainty or variability or possibility variable o Possibly important uncertainty or variability X Probably no important uncertainty or variability o No important uncertainty or variability|We did not search for studies addressing patient values|All outcomes were rated as critical or important with consistent rating among the clinical and patient reviewers| ||||| |Balance of effects Does the balance between desirable and undesirable effects favor the intervention or the comparison?||||

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European Respiratory Journal

|JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| |---|---|---| |o Favors the comparison X Probably favors the comparison either the intervention or the comparison favors the however the intervention or favors the intervention o Probably favors the intervention o Favors the intervention o Varies o Don't know|There is a significant increase in the frequency of adverse events with no clear evidence of clinical benefit, based on the absence of any statistically significant benefit on a critical or important efficacy outcome.|This data does not apply to patients with COPD or asthma who were predominantly excluded from the studies. Approximately 25-40% of patients with bronchiectasis will have coexisting COPD or asthma. The known side effect profile of corticosteroids suggests that a positive evidence base supporting their use is required in order to recommend them. In the absence of any clear evidence of exacerbation or symptom benefit, the balance of risks and benefits would favor avoiding corticosteroids| |Resources required How large are the resource requirements (costs)?||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| |o Large costs o Moderate costs o Negligible costs and savings o Moderate savings o Varies X Don't know|We did not specifically look for studies on resource use.|Inhaled corticosteroids are not highly expensive but are also not lacking in costs and in the absence of clear benefits, if they were used routinely they would incur a modest increase in healthcare costs| |Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)?||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| |o Very low o Low o Moderate High X No included studies|We did not look for studies on resource requirements and so can only infer from what we know of their use in other diseases.|The costs of inhaled corticosteroid medications is well known. The balance of costs and benefits and therefore the cost effectiveness is unknown as there are no cost effectiveness studies and no large studies of effectiveness.| |Cost effectiveness Does the cost-effectiveness of the intervention favor the intervention or the comparison?|||

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|JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| |---|---|---| |o Favors the comparison o Probably favors the comparison o Does not favor either the intervention or the comparison o Probably favors the intervention intervention o Favors the intervention or favors the intervention o Varies X No included studies|We did not look for cost effectiveness studies|| |Equity What would be the impact on health equity?||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| |o Reduced o Probably reduced X Probably no impact o Probably increased o Increased o Varies|We did not search for studies on health equity.|ICS are widely available and so if proven to effective can improve equity compared to more expensive therapies.| |Acceptability Is the intervention acceptable to key stakeholders?||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| |o No o Probably no O Whyes X Yes o Varies o Don't know|Study completion and adherence data suggests that the intervention is acceptable to patient|Acceptability was supported by the patients in the TF. ICS are widely used by clinicians and patients and are well accepted.| |Feasibility Is the intervention feasible to implement?||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| |o No o Probably no O Probably yes X Yes o Varies o Don't know|We did not look for studies assessing feasibility|ICS are widely used by clinicians and patients and are therefore feasible to use.| |SUMMARY OF JUDGEMENTS|||

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|JUDGEMENT|JUDGEMENT|JUDGEMENT|JUDGEMENT|JUDGEMENT|JUDGEMENT|JUDGEMENT|JUDGEMENT|JUDGEMENT| |---|---|---|---|---|---|---|---|---| |PROBLEM|No|Probably no|Probably yes|Yes||Varies|Don't know|| |DESIRABLE EFFECTS|Trivial|Small|Moderate|Large||Varies|Don't know|| |UNDESIRABLE EFFECTS|Large|Moderate|Small|Trivial||Varies|Don't know|| |CERTAINTY OF EVIDENCE|Very low|Low|Moderate|High|||No included studies|| |VALUES|Important uncertainty or variability|Possibly important uncertainty or variability|Probably no important uncertainty or variability|No important uncertainty or variability||||| |BALANCE OF EFFECTS|Favors the comparison|Probably favors the comparison|Does not favor either the intervention or the comparison|Probably favors the intervention|Favors the intervention|Varies|Don't know|| |RESOURCES REQUIRED|Large costs|Moderate costs|Negligible costs and savings|Moderate savings|Large savings|Varies|Don't know|| |CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES|Very low|Low|Moderate|High|||No included studies|| |Cost effectiveness|Favors the comparison|Probably favors the comparison|Does not favor either the intervention or the comparison|Probably favors the intervention|Varies|Varies|No included studies|| |EQUITY|Reduced|Probably reduced|Probably no impact|Probably increased|Increased|Varies|Don't know|| |ACCEPTABILITY|No|Probably no|Probably yes|Yes||Varies|Don't know|| |FEASIBILITY|No|Probably no|Probably yes|Yes||Varies|Don't know||

TYPE OF RECOMMENDATION

|Strong recommendation against the intervention|Conditional recommendation against the intervention|Conditional recommendation for either the intervention or the comparison O|Conditional recommendation for the intervention O|Strong recommendation for the intervention| |---|---|---|---|---|

CONCLUSIONS

Recommendation

Recommendation

We suggest not to offer long term inhaled corticosteroids to patients with bronchiectasis who do not have coexisting COPD or asthma(conditional recommendation against the intervention, low certainty of evidence)

Remarks

•Patients with bronchiectasisshould be evaluated for the presence of co-existing asthma and COPD. The presence of bronchiectasis does not alter the recommendation to use inhaled corticosteroids(ICS) in patients with asthma or in a subset of patients with COPD. Suspected asthma or COPD should be appropriately investigated in patients with bronchiectasis.

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•There is limited evidence suggesting that ICS may be beneficial in a subgroup of patients with bronchiectasis with elevated blood eosinophil counts who do not have asthma or other eosinophilic conditions. However, no recommendation on ICS use based on blood eosinophils is currently possible, and we recommend further research in this group.

The use of ICS should be reevaluated in patients without a clear indication. Discontinuation of ICS may be appropriate in some patients.

Justification

The panel considered there is a lack of evidence of benefit of ICS and a risk of harms associated with this treatment. AEs of ICS are well known and include an increased risk of pneumonia and NTM infection as well as a small but significant increase in systemic adverse effects of corticosteroids. 20-30% of people with bronchiectasis have comorbid asthma or COPD. Treatment with ICS is recommended for most individuals with asthma and for a subset of people with COPD who have elevated blood eosinophils and frequent exacerbations. There is no clear evidence that bronchiectasis should influence the decision to prescribe ICS in these groups.

Blood eosinophils require further investigation in bronchiectasis as a predictor of ICS efficacy. Around 20% of patients with bronchiectasis have blood eosinophil counts>300cells/μl in the absence of asthma or other eosinophilic conditions. There are reports suggesting that in a subset of individuals with elevated blood eosinophils, ICS may be beneficial in improving quality of life and reducing exacerbations but these data are from post hoc analyses and observational studies only and prospective trials are needed.

Subgroup considerations

One study shows a benefit on the St Georges respiratory questionnaire in patients with raised blood eosinophils. In other diseases(COPD/asthma) blood eosinophils are a biomarker of response justifying the use of this biomarker on a case by case basis in patients with bronchiectasis.

Implementation considerations

The use of ICS with or without long-acting beta2 agonists(LABA) is widespread in people with respiratory symptoms, and mislabeling of bronchiectasis as asthma or COPD is not uncommon. Newly diagnosed patients with bronchiectasis may thus be already treated with ICS, and the decision to continue or withdraw ICS when bronchiectasis is diagnosed requires consideration. Factors favoring stopping ICS treatment include the absence of asthma or COPD, supported by established criteria and low blood and sputum eosinophils. On the other hand, every effort should be made to correctly identify asthma in people with bronchiectasis as treatment with ICS has been shown to be beneficial in this population. COPD is frequently misdiagnosed in bronchiectasis patients and the ROSE criteria may support appropriate use of this label in patients with bronchiectasis.

Monitoring and evaluation

If ICS are used, a formal evaluation should be performed after a defined period of time and ICS discontinued if they are not effective. Patients receiving ICS should be evaluated for ICS related adverse effects and treatment discontinued if the risks outweigh theoretical benefits.

Research priorities

A randomized controlled trial of inhaled corticosteroids in people with bronchiectasis is needed to establish if they can reduce the frequency of exacerbations. Such a trial should address whether blood eosinophil counts can predict response.

Since ICS is widely used in bronchiectasis, an alternative study design to investigate the efficacy of ICS is to perform a withdrawal trial in which patients are randomized to withdrawal or continuation of ICS.

Further studies are required to understand the role of T2 inflammation in bronchiectasis(not exclusively limited to blood eosinophils) and whether T2 biomarkers can guide treatment.

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PICO QUESTION 8

|Should pulmonary rehabilitation be used (compared to no pulmonary rehabilitation) in adults with bronchiectasis?|||| |---|---|---|---| |POPULATION:|Adults with bronchiectasis||| |INTERVENTION:|Pulmonary rehabilitation||| |COMPARISON:|No pulmonary rehabilitation||| |MAIN OUTCOMES:|Exacerbations (critical)||| ||Quality of Life (critical)||| ||Symptoms measured using symptom questionnaires or other validated methods (critical)||| ||Mortality (critical)|Mortality (critical)|| ||Severe exacerbations/ Hospitalisations (critical)||| ||Exercise capacity (important)||| ||Activities of daily living (critical)||| ||Breathlessness (critical)||| |SETTING:|OUTPATIENTS WITH BRONCHIJECTASIS||| |PERSPECTIVE:|CLINICAL RECOMMENDATIONS FOR INDIVIDUAL PATIENTS||| |PERSPECTIVE:|Pulmonary rehabilitation is a structured exercise and education intervention to improve quality of life in people with chronic lung disease. All possible modalities for delivering pulmonary rehabilitation programs were included (home / telerehabilitation/ hospital).||| |CONFLICT OF INTERESTS:|None reported|None reported||

ASSESSMENT

|Problem Is the problem a priority?|||| |---|---|---|---| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS|| |o No o Probably no o Probably yes X Yes o Varies o Don't know|It is important to know if pulmonary rehabilitation is an effective intervention for people with bronchiectasis|This intervention is widely used in some countries for people with bronchiectasis|| |Desirable Effects How substantial are the desirable anticipated effects?|||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS|| |o Trivial o Small X Moderate o Large o Varies o Don't know|The pooled data shows an improvement in exercise capacity which is clinically significant at the end of the intervention and an improvement in quality of life. Exacerbations are also reduced based on one study. The improvements predominantly do not persist after the intervention is stopped|Exercise is known to have beneficial effects on general health|| |Undesirable Effects How substantial are the undesirable anticipated effects?||||

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|JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| |---|---|---| |o Large o Moderate o Small O Trivial o Varies X Don't know|We did not specifically look for adverse events as these were not pre-specified outcomes by the panel.This is because exercise and the other components of rehabilitation are not typically associated with adverse events. Worsening of patients condition would be captured through other outcomes including exacerbations and worsening of quality of life. Adverse changes on these outcomes were not observed.|| |Certainty of evidence What is the overall certainty of the evidence of effects?||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| |X Very low o Low o Moderate o High o No included studies|Based on GRADE assessment the certainty of evidence is rated as very low.|Overall the data is highly complex because of different questionnaires, exercise tests and other outcomes used to assess the efficacy of the intervention. Certainty of evidence is low or very low for many outcomes due to risk of bias, inconsistency and imprecision.| |Values Is there important uncertainty about or variability in how much people value the main outcomes?||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| |oImportant uncertainty or variability o Possibly important uncertainty or Optimant o Probably no important uncertainty or X No important uncertainty or variability|We did not search for studies assessing patient values|Patients and clinicians regard exercise capacity, quality of life and exacerbations as very important and there is no uncertainty about this.| |Balance of effects Does the balance between desirable and undesirable effects favor the intervention or the comparison?||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS|

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|X Favors the comparison of OProbably|There are clear beneficial effects of the intervention with improved quality of life and exercise capacity, both above the minimum clinically important difference, and a significant reduction in exacerbations. There is no evidence of downsides to the intervention.|Although pulmonary rehabilitation places a burden on participants and this was considered by the panel, the patient members of the panel considered that the benefits generally outweigh the burden.||| |---|---|---|---|---| |Resources required How large are the resource requirements(costs)?||||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS||| |o Large costs o Moderate costs o Negligible costs and savings o Moderate savings savings o Large savings OVaries X Don't know|We did not look for data on resources required|Proper delivery of pulmonary rehabilitation requires access to appropriate facilities or technological equipment and trained staff and therefore has resource implications||| |||||| |Certainty of evidence of required resources What is the certainty of the evidence of resource requirements(costs)?||||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS||| |o Very low o Low o Moderate o High X No included studies||||| |||||| |Cost effectiveness|Cost effectiveness|Cost effectiveness|Cost effectiveness|Cost effectiveness| |Does the cost-effectiveness of the intervention favor the intervention or the comparison?||||| |JUDGEMENT|RESEARCH EVIDENCE|||| ||||||

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$$\text{Page 162 of 177}$$

|European Respiratory Journal Page 162 of 177|||| |---|---|---|---| |o Favors the Comparison o Probably favors the comparison comparison or Does not favor either the intervention or the comparison o Probably favors the intervention intervention o Varies X No included studies|||| |Equity What would be the impact on health equity?|||| |JUDGEMENT|JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| |o Reduced oProbably oProbably no intervention increased o Varies o Varies|We did not look for studies assessing health equity|As there are important resource implications for PR, there is a risk that a recommendation for PR for bronchiectasis patients would increase health inequalities|| |o Varies X Don't know|||| |Acceptability Is the intervention acceptable to key stakeholders?|||| |JUDGEMENT|RESEARCH EVIDENCE||ADDITIONAL CONSIDERATIONS| |o No o Probably no X Probably o Yes o Varies o Don't know||We did not look for studies assessing acceptability|Patients in general are supportive of PR but not all patients wish to participate particularly associated with logistic barriers(time commitment, social factors,geographic inconvenience,etc)| |Feasibility Is the intervention feasible to implement?|||| |JUDGEMENT|RESEARCH EVIDENCE||ADDITIONAL CONSIDERATIONS| |o No o Probably no X Probably o Yes o Varies o Don't know||We did not search for studies assessing feasibility|Patients in general are supportive of PR but not all patients wish to participate particularly associated with logistic barriers(time commitment, social factors,geographic inconvenience,etc)| |Feasibility Is the intervention feasible to implement?|||| |JUDGEMENT|RESEARCH EVIDENCE||ADDITIONAL CONSIDERATIONS| |o No o Probably no X Probably yes o Yes o Varies o Don't know||We did not search for studies assessing feasibility|Most studies utilized existing PR services designed for patients with COPD and therefore it is clearly feasible to deliver the intervention in some settings Not all countries have widespread access to PR|

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SUMMARY OF JUDGEMENTS

|JUDGEMENT|JUDGEMENT|JUDGEMENT|JUDGEMENT|JUDGEMENT|JUDGEMENT|JUDGEMENT|JUDGEMENT|JUDGEMENT| |---|---|---|---|---|---|---|---|---| |PROBLEM|No|Probably no|Probably yes|Yes||Varies|Don't know|| |DESIRABLE EFFECTS|Trivial|Small|Moderate|Large||Varies|Don't know|| |UNDESIRABLE EFFECTS|Large|Moderate|Small|Trivial||Varies|Don't know|| |CERTAINTY OF EVIDENCE|Very low|Low|Moderate|High|||No included studies|| |VALUES|Important uncertainty or variability|Possibly important uncertainty or variability|Probably no important uncertainty or variability|No important uncertainty or variability||||| |BALANCE OF EFFECTS|Favors the comparison|Probably favors the comparison|Does not favor either the intervention or the comparison|Probably favors the intervention|Favors the intervention|Varies|Don't know|| |RESOURCES REQUIRED|Large costs|Moderate costs|Negligible costs and savings|Moderate savings|Large savings|Varies|Don't know|| |CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES|Very low|Low|Moderate|High|||No included studies|| |Cost effectiveness|Favors the comparison|Probably favors the comparison|Does not favor either the intervention or the comparison|Probably favors the intervention|Favors the intervention|Varies|No included studies|| |EQUITY|Reduced|Probably reduced|Probably no impact|Probably increased|Increased|Varies|Don't know|| |ACCEPTABILITY|No|Probably no|Probably yes|Yes||Varies|Don't know|| |FEASIBILITY|No|Probably no|Probably yes|Yes||Varies|Don't know||

TYPE OF RECOMMENDATION

|Strong recommendation against the intervention|Conditional recommendation against the intervention|Conditional recommendation for either the intervention or the comparison O|Conditional recommendation for the intervention O|Strong recommendation for the intervention| |---|---|---|---|---| |||||X|

CONCLUSIONS

Recommendation

Recommendation

We recommend that patients with breathlessness and/or impaired exercise capacity should be offered pulmonary rehabilitation(strong recommendation for the intervention, very low certainty of evidence)

Remarks

● The educational component of pulmonary rehabilitation(PR) should ideally be bronchietasis specific and include discussion of$$\text{ airway clearance strategies.}$$

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123456789101112121314567892021222324252627282932333435363738394041424344454678920

•Patients with bronchiectasis should be encouraged to undertake regular physical activity, given its multiple health benefits.

Justification

The recommendation is justified by consistent evidence of improvements in quality of life and exercise capacity. Despite the very low certainty of evidence, the strong recommendation is supported by the unequivocal improvement in functional capacity, and consistent results despite small sample sizes. Implementing PR requires substantial investment in resources and trained health professionals, which significantly increases the overall program costs.

Subgroup considerations

No subgroup considerations were identified

Implementation considerations

There are other guidelines describing the proper implementation of pulmonary rehabilitation- 10.1513/AnnalsATS.202102-146ST and DOI: 10.1164/rccm.202306-1066ST

Monitoring and evaluation

In order to monitor rehabilitation quality and patient evolution, an official ATS/REs policy statement advises that clinical outcomes must be measured for individual patients and include a standardized assessment of a patients' functional exercise capacity,dyspnea, and health status.Additionally, an evaluation of other outcomes are suggested such as the impact pulmonary rehabilitation has on psychological comorbidity and measurement of the patients' experience.

Research priorities

Future studies should focus on how we can individualize pulmonary rehabilitation in different settings(home-based, outpatient clinics, hospital-based, community-based and tele-rehabilitation) as well as evaluating digital tools that could replace face to face rehabilitation. Research should also try to tackle the impact of pulmonary rehabilitation applied during or immediately after an acute exacerbation. Finally, evaluating pragmatic strategies

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PICO QUESTION 6

|Should eradication treatment be used for patients with isolation of a new pathogenic microorganism|| |---|---| |$$\text{POPULATION:}$$|Patients with a new or recurrent isolation of a pathogenic microorganism| |INTERVENTION:|Eradication treatment for a new pathogenic microorganisms| |MAIN OUTCOMES:|No eradication treatment(symptomatic treatment only)| |MAIN OUTCOMES:|Exacerbations(critical)| |MAIN OUTCOMES:|Quality of life(critical)| |MAIN OUTCOMES:|Symptoms measured using symptom questionnaires or other validated methods(critical)| |MAIN OUTCOMES:|Mortality(critical)| |MAIN OUTCOMES:|Adverse events(critical)| |MAIN OUTCOMES:|Severe exacerbations/hospitalization(critical)| |MAIN OUTCOMES:|Resistance(important)| |MAIN OUTCOMES:|Sputum culture conversion(defined as sputum culture becoming negative for the target pathogen)(critical)| |MAIN OUTCOMES:|PRIMARY OR SECONDARY CARE| |MAIN OUTCOMES:|CLINICAL RECOMMENDATIONS FOR INDIVIDUAL PATIENTS| |MAIN OUTCOMES:|BACKGROUND:| |MAIN OUTCOMES:|CONFLICT OF INTERESTS:| |MAIN OUTCOMES:||

ASSESSMENT

|Problem|Problem|| |---|---|---| |Is the problem a priority?||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| |o No o Probably no o Probably yes X Yes oVaries o Don't know|Chronic Pseudomonas infection is associated with poor clinical outcomes therefore preventing chronic Pseudomonas is a priority|Patients are aware of P. aeruginosa as a clinical problem and see its treatment and prevention as a key consideration.| |Desirable Effects How substantial are the desirable anticipated effects?||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| |o Trivial o Small|The pooled estimate from our meta-analysis of eradication is 41.5% clear of Pseudomonas at 1 year. This is clinically important. Interpretation of this data is limited by the lack of a control group and therefore not knowing what the clearance rate would be in a control group|There is limited data for other outcomes of interest such as exacerbations and longer term outcomes over 5 or 10 years are not reported in any studies.| |Undesirable Effects How substantial are the undesirable anticipated effects?||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS|

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|European Respiratory Journal||| |---|---|---| |||| |o Large Studies did not report adverse events in any interpretable way Antibiotic treatments have a high treatment burden, a high risk of antibiotic o Small 0 Small o Trivial 5 O Varies o Fories||| |||| |Certainty of evidence What is the overall certainty of the evidence of effects?||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| |X Very low o Low o Moderate o High included studies|Based on GRADE assessment|The evidence base is limited to a small number of before and after studies which indirectly suggest PA eradication is possible| |Values Is there important uncertainty about or variability in how much people value the main outcomes?||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| |o Important uncertainty or variability or variability of the results in 50|We did not search for studies assessing patient values|Exacerbations, clearance of PA, hospitalisations etc are all regarded as important by clinicians and patients.| |important uncertainty or Supplementary variability uncertainty or Uncertainty or variability on 45 Int 20 54||| |X No important uncertainty or variability||| |Balance of effects Does the balance between desirable and undesirable effects favor the intervention or the comparison?||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS| |o Favors the comparison o Probably favors the comparison the comparison otherwise the intervention or favors the intervention o Varies|The evidence base is so poor that this is a difficult question to answer but as the impact of chronic PA is known to be severe, and the data suggests that clearance is possible in approximately 40% of cases,|This is also informed by feedback from patients on the importance of the goal of this treatment and their views on the risks vs benefits and treatment burden. We feel most patients would choose to try eradication rather than to take standard care alone. This is reflected in previous recommendations from guidelines as well as indirect evidence from cystic fibrosis.|

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|o Don't know|||| |---|---|---|---| |o Don't know|||| |Resources required How large are the resource requirements (costs)?|||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS|| |o Large costs o Moderate costs o Negligible costs and savings o Moderate savings o Large savings o Varies X Don't know|We did not search for studies on required resources|The most effective intervention seems to include inhaled antibiotics and this requires some cost and infrastructure. The costs are not insignificant.|| |Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)?|||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS|| |o Very low o Low o Moderate x No Included studies|We did not search for studies on required resources||| |Cost effectiveness|Cost effectiveness|Cost effectiveness|| |Does the cost-effectiveness of the intervention favor the intervention or the comparison?|||| |JUDGEMENT|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS|| |o Favors the comparison o Probably favors the comparison o Does not favor the comparison o Probably favors the intervention o Favors the|We did not search for studies on cost-effectiveness|There is no cost effectiveness analysis and as treatment can consist of oral antibiotics, IV antibiotics or inhaled antibiotics the costs will vary dramatically depending on the type of intervention used.||

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||||||||| |---|---|---|---|---|---|---|---| |intervention o Varies|||||||| |X No included studies|||||||| ||||||||| |Equity What would be the impact on health equity?|||||||| |JUDGEMENT|JUDGEMENT|RESEARCH EVIDENCE|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS|||| |o Reduced o Probably no reduced in impact|We did not look for studies addressing health equity|No additional considerations|||||| |o Probably no increased|||||||| |o Varies X Don't know|||||||| |Acceptability Is the intervention acceptable to key stakeholders?|||||||| |JUDGEMENT|JUDGEMENT|RESEARCH EVIDENCE|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS|||| |o No o Probably no X Probably yes o Yes o Varies o Don't know|We did not search for studies on acceptability|Patients are able to take this treatment and some may want to do so. Poor adherence to inhaled antibiotics in particular suggests it is not acceptable to all patients. IV antibiotics may require an inpatient stay which will not be acceptable to all patients.|||||| |Feasibility Is the intervention feasible to implement?|||||||| |JUDGEMENT|JUDGEMENT|RESEARCH EVIDENCE|RESEARCH EVIDENCE|ADDITIONAL CONSIDERATIONS|||| |o No o Probably no o Proably yes X Yes o Varies o Don't know|||This is an intervention that is widely practiced.||||| |Acceptability|Acceptability|Acceptability|Acceptability|Acceptability|Acceptability|Acceptability|| |JUDGEMENT|JUDGEMENT|RESEARCH EVIDENCES|RESEARCH EVIDENCES||||| |o No o Probably no O varies o Don't know|||||||| |SUMMARY OF JUDGEMENTS|||||||| ||||||||| |PROBLEM|No|Probably no|Probably yes|Yes||Varies|Don't know| |DESIRABLE EFFECTS|Trivial|Small|Moderate|Large||Varies|Don't know| |UNDESIRABLE EFFECTS|Large|Moderate|Small|Trivial||Varies|Don't know| |CERTANTY OF EVIDENCE|Very low|Low|Moderate|High|||No included studies|

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|JUDGEMENT|JUDGEMENT|JUDGEMENT|JUDGEMENT|JUDGEMENT|JUDGEMENT|JUDGEMENT|JUDGEMENT|JUDGEMENT| |---|---|---|---|---|---|---|---|---| |VALUES|Important uncertainty or variability|Possibly important uncertainty or variability|Probably no important uncertainty or variability|No important uncertainty or variability||||| |BALANCE OF EFFECTS|Favors the comparison|Probably favors the comparison|Does not favor either the intervention or the comparison|Probably favors the intervention|Favors the intervention|Varies|Don't know|| |RESOURCES REQUIRED|Large costs|Moderate costs|Negligible costs and savings|Moderate savings|Large savings|Varies|Don't know|| |CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES|Very low|Low|Moderate|High|||No included studies|| |Cost effectiveness|Favors the comparison|Probably favors the comparison|Does not favor either the intervention or the comparison|Probably favors the intervention|Favors the intervention|Varies|No included studies|| |EQUITY|Reduced|Probably reduced|Probably no impact|Probably increased|Increased|Varies|Don't know|| |ACCEPTABILITY|No|Probably no|Probably yes|Yes||Varies|Don't know|| |FEASIBILITY|No|Probably no|Probably yes|Yes||Varies|Don't know||

TYPE OF RECOMMENDATION

|Strong recommendation against the intervention|Conditional recommendation against the intervention|Conditional recommendation for either the intervention or the comparison O|Conditional recommendation for the intervention|Strong recommendation for the intervention| |---|---|---|---|---| ||||X|O|

CONCLUSIONS

Recommendation

Recommendation

We suggest to offer eradication treatment to patients with a new isolation of Pseudomonas aeruginosa(conditional recommendation for the intervention, very low certainty of evidence)

Remarks

● A new isolation of P.aeruginosa may refer to the first time a patient has P. aeruginosa isolated or a further isolation following a prolonged period during which P. aeruginosa was not detected.

● Eradication practices vary both among panel members and globally. Some clinicians prescribe systemic antibiotics(e.g 2-week course) followed by a repeat sputum culture, discontinuing antibiotics if the sample is negative. Others would add inhaled antibiotics for 4 weeks to 3 months, without rechecking sputum cultures. The 2017 ERS guidelines provide examples of different antibiotic strategies.

Justification

European Respiratory Journal

Page 170 of 177

Despite limited available data, there is overwhelming evidence that chronic infection with P. aeruginosa is associated with increased mortality, exacerbations,19 participants and worse quality of life. Preventing chronic P. aeruginosa infection is, therefore, of high benefit to patients, and this was confirmed by our panel members with lived experience. The conditional recommendation reflects both the very low certainty of evidence and the concern that while 40% achieve eradication 198 treatment carries burden, particularly if inhaled antibiotics are used, and antibiotic use is associated with a risk of antimicrobial resistance and side effects.

Subgroup considerations

The recommendation applies exclusively to eradication of Pseudomonas aeruginosa as no data was identified for other microorganisms. The panel does not practice eradication of other microorganisms.

Implementation considerations

The 2017 ERS guidelines provides examples of antibiotic regimens for eradication which typically consist of 2 weeks of oral or IV antibiotics followed by 6 weeks to 3 months of inhaled antibiotics. Practice varies in terms of the antibiotics used, and whether some clinicians will check sputum cultures after the systemic antibiotic phase and discontinue treatment if sputum is negative, while some clinicians will use inhaled antibiotics regardless of whether initial culture conversion is achieved after systemic antibiotics.

Monitoring and evaluation

Patients who undergo an eradication regimen should have sputum samples performed after the eradication treatment is completed and at 1 year to confirm if eradication has been successful. Patients who fail to achieve eradication should be treated as chronic P. aeruginosa infection.

Research priorities

A randomized controlled trial of P. aeruginosa eradication vs symptomatic treatment only should be performed to establish the long term efficacy and safety of this practice.

Studies utilising molecular techniques to detect P. aeruginosa should be performed to identify if the organism is truly eradication or just suppressed.

Evidence to Decisions(EtD) framework Page 171 of 177

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Narrative question 2

|Domain|Judgement|Research evidence|| |---|---|---|---| |7|o No|Exacerbations are a cause of significant morbidity and sometimes mortality, and are desirable to prevent. Patients regard exacerbations as highly distressing and important to prevent and treat.There is some heterogeneity in the definition of exacerbations. Therefore, diagnostic tests are important in the management of exacerbations and as they impact morbidity and mortality,interventions are also very important.|The patient members of the guideline panel identified the management of exacerbations as one of the most impactful aspects for their daily lives.| |Certainty of evidence|What is the overall certainty of the evidence of effects? X Very Low o Low|The certainty of evidence is very low. We did a narrative review of the evidence. The included guidelines are mainly based on expert opinion and good clinical practice for the diagnostic questions.|| ||o Moderate o High o No included studies||| |Current practice||Current practice is to diagnose exacerbations based on an acute worsening of respiratory symptoms in patients with bronchiectasis(with no uniform definition used globally) and to treat with 14 days of antibiotics. Sputum culture is recommended by all guidelines that address this topic and they suggest to do this baseline with modification of therapy based on isolated microbes and sensitivity results.|In real life clinical practice some exacerbations, particularly when mild or associated with antibiotic sensitive pathogens (e.g S. pneumoniae) are treated with 7 days of antibiotic treatment with good results. Sputum culture is frequently not available and so most prescribing is empirical based on prior results or on what has "worked" for patients in the past.|

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|1 2 3 4 5 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43|Values|Is there important uncertainty about or variability in how much people value the main outcomes? o Important uncertainty or variability|All recommendations and all data suggest that there is consensus that the main outcome of exacerbation management and the diagnostics and interventions used are valued highly in the overall management. The fact that exacerbation is a main outcome in almost every clinical trial accentuates this.|A survey of patients performed by EMBARC in 2015/16 Page 172 of 177 found 70% or more of patients regard exacerbations as difficult or very difficult with less than 10% of patients reporting this as not an issue.| |---|---|---|---|---| |1 2 3 4 5 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43|Values||o Possibly important or variability|| ||o Probably no important uncertainty or variability|||| |Summary of evidence/ Benefits and harms|How substantial are the benefits of the intervention compared to harms?|Recommendations in current guidelines regarding diagnostics focus on timing of sputum sampling, clinical examination and additional investigations that might help to assert the diagnosis of an exacerbation. They include a statement on the definition of an exacerbation as well as recommendations on how to recognize severe exacerbations.Recommendations in current guidelines regarding interventions are focused on antibiotics, mainly their timing, duration, administration and type.||| |Equity|What would be the impact on health equity?|The recommendations in current guidelines literature are easily applied across different settings both geographically and economically. One|…||

|Page 173 of 177|O Reduced o Probably reduced o Probably no impact X Probably increased o Varies o Don't know|economically poorer regions.In that respect, health equity is being considered in the current guideline literature.|| |---|---|---|---| |Acceptability|Is the intervention acceptable to key stakeholders? o No o Probably no O Probably yes X Yes o Varies o Don't know|Stakeholders currently accept the guidelines as trials designed by healthcare providers or industry include many aspects of the guidelines (sputum collection at exacerbation, definition of exacerbation, investigations to determine severe exacerbation, antibiotic choice, etc) in their policies, trials and local guidelines. Other aspects of exacerbation diagnostics and interventions are accepted as they are a vital aspect of the disease that needs adequate management and involvement by all stakeholders.||

|1||Features of a severe exacerbation (defined as requiring hospitalization or intravenous antibiotic treatment) may include tachypnoea, acute or acute on chronic respiratory failure, a significant decline in oxygen European Respiratiou Journal, hypercapnia, hemotypis, new onset of cyanosis, new signs of cor pulmonale, hemagenet 74 of 177 instability,and/or impaired cognitive function.| |---|---|---| |1|• At the onset of an exacerbation, a sputum sample for microbeology should ideally be obtained before initiating antibiotic treatment. 5|Features of a severe exacerbation (defined as requiring hospitalization or intravenous antibiotic treatment) may include tachypnoea, acute or acute on chronic respiratory failure, a significant decline in oxygen European Respiratiou Journal, hypercapnia, hemotypis, new onset of cyanosis, new signs of cor pulmonale, hemagenet 74 of 177 instability,and/or impaired cognitive function.| |3||• Sputum culture should be repeated, where possible, if there is no response to the initial antibiotic treatment.| |4||We suggest the following interventions to be performed during exacerbations(conditional recommendation for the intervention, very low certainty of evidence based on a narrative review of evidence):| |5||Recommendations in current guidelines regarding interventions endorsed by the panel: Antibiotics should be prescribed for an exacerbation, guided by previous microbiology results, local susceptibility patterns, and clinical severity. ● An adult bronchiectasis self-management plan should include guidance on recognising exacerbations. Providing selected patients the ability to self-administer antibiotics at home with appropriate instruction and education, may allow more prompt treatment. ● Patients not responding promptly to oral antibiotics or showing signs of a severe exacerbation, should be reviewed to determine if there is a need for a change in treatment, intravenous antibiotic treatment and/or hospitalization. ● Airway clearance regimens may need to be adapted in frequency, intensity, and technique during an exacerbation. ● In general, a 14-day antibiotic course is considered standard, especially in severe exacerbations or in patients with P. aeruginosa infection. Shorter courses may be appropriate in patients with mild bronchiectasis, those with infection due to pathogens more sensitive to antibiotics (e.g. S. pneumoniae), or patients with a rapid return to baseline symptoms during treatment.| |1 12||• In general, a 14-day antibiotic course is considered standard, especially in severe exacerbations or in patients with P. aeruginosa infection. Shorter courses may be appropriate in patients with mild bronchiectasis, those with infection due to pathogens more sensitive to antibiotics (e.g. S. pneumoniae), or patients with a rapid return to baseline symptoms during treatment.| |1 14|Justification|Despite the very low quality of evidence, the recommendations are justified as many of the suggested practices are already routinely implemented in hospitals managing patients with bronchiectasis. While specific antibiotic regimens are not detailed due to variations in local practice and resistance patterns, general principles for management of exacerbations can still be established to guide clinical decision-making.| |1 16|Subgroup considerations|Subgroup consideration are mentioned in current guideline literature, targeting patients with Pseudomonas aeruginosa, patients who fail to respond to oral antibiotic treatment and patients with severe exacerbations.| |1 18|Implementation consideration|The implementation of these recommendations is expected to be straightforward, as they are generally inexpensive and already widely integrated into clinical practice. Given their broad acceptance and routine use in most settings, additional resource allocation or infrastructural changes are unlikely to be necessary for widespread adoption.| |2 21|Monitoring and evaluation|Exacerbations are common and important events in the natural history of bronchiectasis. Monitoring and evaluation should prioritise assessing their frequency, severity, and response to interventions. Prevention of exacerbations is a major priority and therefore in addition to the acute management of exacerbations patients should be reviewed to determine if they are at high risk of future exacerbations, and preventative measures is implemented to reduce future risk.| |2 23||Are a high risk of future exacerbations, and preventative measures is a major priority and therefore in addition to the acute management of exacerbations patients should be reviewed to determine if they are at high risk of future exacerbations, and preventative measures is implemented to reduce future risk.| |2 25||Future research should be focused on the following topics: i) Assessing the presence, severity, and evolution of bronchiectasis exacerbations; ii) Determining the optimal antibiotic management, especially regarding monotherapy versus dual antibiotics and evaluating the role of inhaled antibiotics during exacerbations; iii) Investigating the role of non-antibiotic treatments and identifying causes of exacerbations other than bacterial infection; iv) Establishing the optimal duration of antibiotic treatment particularly for outpatients v) identification of biomarkers that can allow shortening or individualising of antibiotic treatment duration.| |2 27||| |2 30||| |3 27||| |3 32||| |3 33||| |3 44||| |3 6||| |3 7||| |3 8||| |39||| |40||| |41||| |42||| |43||| |44||| |45|Downloaded from https://publications.ersnet.org on September 29, 2025 by guest. Please see licensing information on first page for reuse rights.||

Narrative Question 3: What investigations and treatments are currently recommended in a patient with bronchiectasis who is rapidly deteriorating in terms of symptoms or exacerbations?

Domain

Judgement

Research evidence

Priority

Is the Problem a priority

○ No

○ Probably no○ Probably yes X Yes

○ Varies

○ Don't know

Rapidly deteriorating patients are a group that is

rarely explicitly mentioned in the current guidelines. Most guidelines indirectly mention guidance in

patients who are deteriorating. However current

guidelines in literature are a priority as substantial mortality follow from patients who are rapidly

deteriorating.

The patient members of the panel considered rapid deterioration a priority

C 3ertainty of evidence What is the overall

certainty of the

evidence of effects?X Very Low

○ Low

○ Moderate

○ High

○ No included studies

The evidence is based on a narrative review of

existing guideline recommendations, many of which are based on expert opinion or extrapolation for

other clinical situations. Therefore the certainty of evidence as a whole is considered very low, even if individual components of the interventions

recommended may have a stronger evidence base.

Current practice

Current practice for rapidly deteriorating patients is based on an acute worsening of respiratory

symptoms in patients with bronchiectasis (with no uniform definition used globally). Currently, patients with rapid deterioration, are advised to be referred to a specialist clinic. A reevaluation of treatment is performed and critically appraised. Serious

symptoms or end-stage disease are managed

accordingly and are in line with the

recommendations mentioned in this summary.

Based on the discussion with the task force panel, current

practice for rapidly deteriorating patients is inconsistent

between different healthcare providers. There is no uniform definition of what represents deterioration or disease

progression.

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Values

Is there important

uncertainty about or

variability in how much people value the main outcomes?

○ Important uncertainty or variability

○ Possibly important

uncertainty or

variability

○Probably no important uncertainty or

variability

X Not important

uncertainty or

variability

○ No known undesirable

outcomes

All relevant stakeholders acknowledge the

importance of rapid disease deterioration as it

causes significant mortality and morbidity. Therefore there is no important uncertainty of variability in

how much people/stakeholders value these

outcomes.

Patients expect that if their health status is rapid worsening they would receive expedited investigations and treatment.

Summary of evidence/ Benefits and harms

How substantial are the benefits of the

intervention compared to harms?

○ Trivial

○ Small

○ Moderate

X Large

○ Varies

○ Don't know

The current guidelines in literature on investigations in deteriorating patients focuses on a good baseline characterization to able to assess deterioration in

the future. This also entails reevaluation of etiology, current treatment and preventive measures in case of deterioration.

In terms of recommendations in current guideline

literature on treatments, referral to a specialist clinic is key where current treatment will be reassessed.

Also timely referral for hospitalization in case of

deterioration of severe exacerbation or if surgery or transplantation needs to be considered, is essential.

Large is selected here partly based on patient feedback that it would be completely inappropriate to not intervene in a patient who is rapidly worsening.

Equity

What would be the impact

The recommendations in current guidelines

literature are easily applied across different settings both geographically and economically. Especially the

…

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on health equity?

○ Reduced

○ Probably reduced○ Probably no impact X Probably increased○ Increased

○ Varies

○ Don't know

timely referral in deteriorating patients to specialist bronchiectasis centers could improve health equity.

Acceptability

Is the intervention acceptable to key stakeholders?

○ No

○ Probably no

○ Probably yes

X Yes

○ Varies

○ Don't know

Deterioration of symptoms is a vital aspect of the disease that needs adequate management and

involvement by all stakeholders. Current guidelines in literature involve different stakeholders. Both

investigations and treatments for deteriorating

patients with bronchiectasis is a multidisciplinary endeavor where all stakeholders are involved.

Patients expect that is their health status is deteriorating rapidly that there would be immediate intervention to

identify the cause and provide treatment.

Narrative question:

TYPE OF

RECOMMENDATION

Strong recommendation against the intervention o

Conditional

recommendation against the

intervention

o

Conditional

recommendation for

either the intervention or the alternative

o

Conditional

recommendation for the intervention

X

Strong recommendation for the intervention

o

Recommendation

We suggest the following investigations and management in a deteriorating patient (conditional recommendation for the intervention, very low certainty of evidence based on a narrative review of evidence):

Recommendations in guideline literature on investigations in the deteriorating patient endorsed by the panel:

• Clinical deterioration including increasing exacerbation frequency and/or severity, worsening of symptoms and/or rapid decline in lung function, should result in a comprehensive re-evaluation of the patients and their treatment.

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• Adherence to both airway clearance techniques and/or pharmacological treatment should be evaluated.

• Underlying diseases other than bronchiectasis should be reviewed to ensure they are being adequately treated.

• Investigation for specific conditions known to be associated with deterioration (e.g ABPA, NTM infection or infection with a new pathogen) should be considered.

• Early diagnosis of bronchiectasis, accurate identification and treatment of its underlying cause, adequate management of chronic airway infection, and interventions to prevent exacerbations and control disease may delay disease progression.

• Repeat chest CT imaging can help to identify several potential causes of deterioration.

• Repeat testing for NTM should be performed when there are suggestive clinical or radiologic features of NTM infection, particularly in those who deteriorate despite appropriate antibiotics.

Recommendations in guideline literature on treatments endorsed by the panel:

• Deteriorating patients who are not already under the care of a bronchiectasis specialist should be referred to a respiratory clinic with expertise in bronchiectasis.

• Current treatment should be reviewed and optimised using a “treatable traits” approach. This includes, but is not limited, to treatment directed at the underlying aetiology of the patients bronchiectasis, airway clearance and mucoactive treatments, vaccination status, long-term (inhaled or oral) antibiotic treatment, P. aeruginosa eradication treatment, long-term inhaled bronchodilator and corticosteroid treatment, pulmonary rehabilitation, oxygen therapy and non-invasive ventilatory support where appropriate.

• Lung resection may be considered in highly selected patients with localised disease whose symptoms are not controlled by medical treatment optimised by a bronchiectasis specialist.

• Early referral for lung transplantation is essential in patients with progressive disease despite optimal medical management. This may include rapidly declining FEV1 or FEV1 <30%predicted, and/or PaCO2 >50mmHg.

Justification

Rapid deterioration in patients with bronchiectasis represents a critical aspect of the disease spectrum, necessitating timely recognition and appropriate management. While most current guideline literature, with the exception of the British Thoracic Society guidelines, do not provide specific guidance for the deteriorating patient, many existing recommendations are applicable to those experiencing increasing exacerbations or worsening symptoms and we therefore extracted these recommendations. These include guidance on follow-up strategies, treatment optimisation, and prevention measures to mitigate disease progression.

The accumulated evidence supports early investigation and proactive treatment of patients who have deterioration. By applying these general principles from existing guidelines, clinicians can ensure that deteriorating patients receive timely and individualised management, potentially reducing morbidity and improving long-term outcomes.

Subgroup considerations

Current subgroup recommendations are made for patients with specific deterioration of a symptom, such as significant increase in hemoptysis, significant shortness of breath with

need for oxygen or non-invasive ventilation as well as recurrent infections due to chronic infection.

Implementation consideration As with all aspects of bronchiectasis care the approach to the deteriorating patient must be personalised and adapted based on the nature of the deterioration, the signs and symptoms presenting and the patients treatable traits. The approach to deteriorating symptoms and reduced lung function may be different as will specific situations such as, a marked increase in haemoptysis, worsening shortness of breath requiring oxygen or non-invasive ventilation, and recurrent exacerbations due to chronic bacterial infections.

Monitoring and evaluation

Monitoring and evaluation should focus on early identification and timely intervention for patients experiencing disease deterioration, as this is a common feature of bronchiectasis. Regular clinical assessment, symptom tracking, and objective investigations should be prioritized to detect worsening conditions and guide appropriate treatment. Key aspects of

monitoring include evaluating exacerbation frequency, respiratory function decline, increased need for oxygen or ventilatory support, and persistent infections

Research priorities

Future research should focus on:-

Improving diagnostic tools to enable faster identification, severity assessment, and objective follow-up of deteriorating patients with bronchiectasis.

-

Determining the optimal timepoint for hospitalisation referral, as well as referral for surgery or lung transplantation.

-

Establishing strategies for measure end-of-life care and palliative management in patients with advanced bronchiectasis.

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