Term Macrolides in Adults with Respiratory Disease

Respiratory infection BMJ Open Resp Res: first published as 10.1136/bmjresp-2019-000489 on 23 April 2020. Downloaded from British Thoracic Society guideline for the use of long-term macrolides in adults with respiratory disease

David Smith,1 Ingrid A Du Rand,2 Charlotte Addy,3 Timothy Collyns,4 Simon Hart,5 Philip Mitchelmore,6 Najib Rahman,7 Ravijyot Saggu8

To cite: Smith D, Du Rand IA, Abstract In addition, the Guideline Development Addy C, et al. British Thoracic The full British Thoracic Society (BTS) guideline for the Group (GDG) has looked at safety issues Society guideline for the use of use of long-term macrolides in adults with respiratory surrounding the long-term use of macro- long-term macrolides in adults disease is published in Thorax. The following is a with respiratory lides at both patient and population levels summary of the recommendations and good practice to help to formulate pragmatic guidance in disease. BMJ Open Resp Res points. The sections referred to in the summary refer to 2020;7:e000489. doi:10.1136/ the full guideline. The appendices are available in the full this area based on the best available evidence bmjresp-2019-000489 guideline and online appendices are available on the BTS combined with clinical experience. website. This is the first BTS guideline to use the Grading Received 5 September 2019 of Recommendations, Assessment, Development and Accepted 6 September 2019 Target audience for the guideline Evaluations (GRADE) approach as part of the process of guideline development and the guideline was used to pilot The guidelines will be of interest to the the new methodology. UK-based clinicians caring for adults with respiratory disease, including respiratory copyright. physicians, acute/general medicine physicians and respiratory specialist nurses. The Introduction guidelines may also be of interest to general The full guideline for the use of long-term practitioners, community matrons and prac- macrolides in adults with respiratory disease is 1 tice nurses, hospice staff and community published in Thorax. The key features of the respiratory teams, physiotherapists, micro- methodology and guideline are highlighted

biologists, pathologists, pharmacists, haema- http://bmjopenrespres.bmj.com/ in a short article published to accompany the tologists and lung transplant teams. full guideline.2 The following is a summary of the recommendations and good practice points (GPPs). The sections referred to in the Areas covered by the guideline summary refer to the full guideline. This guideline covers the following respiratory conditions: asthma, bronchiectasis, chronic obstructive pulmonary disease Background (COPD), bronchiolitis obliterans, chronic The aim of this guideline was to examine the cough, organising pneumonia and diffuse evidence for the use of long-term, low-dose panbronchiolitis. macrolide agents used in the therapy of adult

The guideline excludes paediatric prac- on April 24, 2020 by guest. Protected respiratory diseases, to develop guidance for tice. The use of macrolides in cystic fibrosis clinicians in the use of these agents. has not been included recognising the The guideline covers the use of macrolide parallel work of the National Institute for in adults (>16 years) where the duration of © Author(s) (or their Health and Care Excellence 3 in this area. employer(s)) 2020. Re-use treatment exceeds that usually employed to Long-term macrolides for chronic rhinosi- permitted under CC BY-NC. No treat an acute infection and the dosage is commercial re-use. See rights nusitis have not been included. The use of less than that usually employed to treat an and permissions. Published by macrolides as antibacterial agents to treat BMJ. acute infection. Such usage is considered respiratory infection is excluded. For numbered affiliations see to be exerting an effect through mecha- end of article. nisms other than a direct antibacterial one, Correspondence to commonly described as immunomodulatory Methodology Dr David Smith; mechanisms. We have characterised this as This is the first British Thoracic Society (BTS) david.smith@nbt.nhs.uk long-term, low-dose usage. guideline to use the GRADE approach as

Smith D, et al. BMJ Open Resp Res 2020;7:e000489. doi:10.1136/bmjresp-2019-000489 1 Open access BMJ Open Resp Res: first published as 10.1136/bmjresp-2019-000489 on 23 April 2020. Downloaded from

Table 1 Summary of outcome measures Population Intervention Control Outcomes

Adults with asthma Long-term, Placebo ►► Quality of life measures Adults with bronchiectasis low-dose ►► Symptom improvement/symptom score macrolides ►► Exacerbation rates Adults with COPD ►► Hospital admission rate Adults with bronchiolitis obliterans ►► Disease progression and changes in lung function Adults with chronic cough tests ►► Mortality Adults with organising pneumonia ►► Exercise capacity/tolerance Adults with diffuse panbronchiolitis ►► Sputum volume/colour/character and microbiological resistance/dysbiosis ►► Drug monitoring/side effects/toxicity

COPD, chronic obstructive pulmonary disease. part of the process of guideline development. Previous In line with GRADE, a series of patient-centred guidelines have used the SIGN methodology. BTS has outcomes were identified by the group when the scope made this change to reflect common practice in guide- was agreed (see table 1). line development internationally across all medical specialities. The advantages of the GRADE approach are Appraisal and grading of evidence described in detail in the GRADE handbook and the BTS Each relevant paper was appraised by outcome(s), to GRADE guideline production manual (https://www.brit- thoracic.org.uk/quality-improvement/guidelines/). generate the best estimate of the effect on each outcome An accompanying article has been published in Thorax and an index of the uncertainty associated with that which provides additional background.2 estimate where possible. An evidence profile entry was completed for each outcome which included grading of copyright. the quality of the evidence. The type of evidence available Clinical questions, patient centred outcomes and for each outcome varied from systematic reviews to case literature search series; for each outcome, the highest-quality evidence avail- Clinical questions were formulated in the PICO (patient, able was included. GRADEpro was used to generate the intervention, comparison and outcome) format. The evidence profiles, published online on the BTS website PICO framework was used to define the scope of the where they are available for review (see online appendix guideline and formed the basis of the literature search. 2). The GRADE approach to rating the quality of evidence The initial search was completed in February 2017, with begins with the study design (table 2) and then, through http://bmjopenrespres.bmj.com/ a subsequent search perfumed later in 2017 by York a process of considered judgement, applies five reasons University. Systematic electronic database searches were to possibly rate down the quality of evidence and three conducted to identify all papers which might poten- reasons to possibly rate up the quality (table 3). tially be included in the guideline. For each question, In assessing the evidence, the GDG combined low the following databases were searched: Cochrane Data- and very low evidence into one category (low) as the base of Systematic Reviews, Database of Abstracts of body of evidence was limited. Reviews of Effects, Health Technology Assessment Data- base, Cochrane Central Register of Controlled Trials, MEDLINE and MEDLINE In-Process, Embase and Drafting the guideline and making recommendations PubMed. The search strategy is available for review in The GDG reviewed each clinical question during the online appendix 1. regular meetings and consensus was reached. Having on April 24, 2020 by guest. Protected

Table 2 Categories of evidence Characteristics Confidence High Based on consistent results from well-performed Further research is very unlikely to change the estimate of the effect randomised controlled trials Moderate Based on randomised controlled trials where there is Further research is likely to have an impact on the estimate of the evidence of bias, or from other well-conducted study effect types (eg, well-executed observational studies) Low Based on observational evidence, or from controlled Further research is likely to have an important impact trials with several serious limitations Very low Based on case studies or expert opinion Estimates of effect are far from certain and more research is needed

2 Smith D, et al. BMJ Open Resp Res 2020;7:e000489. doi:10.1136/bmjresp-2019-000489 Open access BMJ Open Resp Res: first published as 10.1136/bmjresp-2019-000489 on 23 April 2020. Downloaded from

Table 3 Decreasing and increasing the grade of evidence

Decrease grade if* ►► Serious or very serious limitation to study quality ►► Important inconsistencies in results ►► Some or major uncertainty about directness of the evidence ►► Imprecise or sparse data (relatively few participants and/or events) ►► High probability of reporting bias Increase grade if ►► Magnitude of the treatment effect is very large and consistent ►► Evidence of a large dose-response relation ►► All plausible confounders/biases would have decreased the magnitude of an apparent treatment effect

*Each quality criterion can reduce the quality by one or, if very serious, two levels. See BTS GRADE guideline production manual for further details (https://www.brit-thoracic.org.uk/quality-improvement/guidelines/). BTS, British Thoracic Society.

Table 4 Explanation of the terminology used in BTS recommendations Strength Benefits and risks Implications Strong. It is recommended and so Benefits appear to outweigh the risks (or Most service users would want to or ‘offer’ vice versa) for the majority of the target should receive this intervention group Conditional. It is suggested and so Risks and benefits are more closely The service users should be supported ‘consider’ balanced, or there is more uncertainty in to arrive at a decision based on their likely service users values and preferences values and preferences

BTS, British Thoracic Society. generated evidence profiles for each of the clinical ques- Summary of recommendations and GPPs tions, the GDG as a whole then considered the impor- Asthma tance of each of the outcomes for each clinical question Recommendations and proceeded to grade the overall body of evidence for ►► Oral macrolide therapy could be considered to reduce copyright. critical and important outcomes. exacerbation frequency in adults (50–70 years) with The GDG went on to decide on the direction and ongoing symptoms despite >80% adherence to high- strength of recommendations considering the quality of dose inhaled steroids (>800 µg/day) and at least one the evidence, the balance of desirable and undesirable exacerbation requiring oral steroids in the past year. outcomes, and the values and preferences of patients and This recommendation reflects the population within others. GRADE specifies two categories of strength of a the AMAZES randomised controlled trial (RCT) recommendation as presented in table 4.

which represents the highest-quality evidence of http://bmjopenrespres.bmj.com/ From the outset, it was acknowledged that there would macrolide therapy leading to a significant reduction be little high-quality evidence for some of the clinical in exacerbations. (Conditional) questions identified. GPPs were developed by consensus ►► Treatment with azithromycin should be considered in areas where there was no quality evidence but the GDG for a minimum of 6–12 months to assess evidence of felt that some guidance based on the clinical experience efficacy in reducing exacerbations. (Conditional) of the GDG might be helpful to the reader. These are ►► Oral macrolide therapy should not be offered as a indicated as shown below. way to reduce oral steroid dose; in some individuals, this may result as a consequence of a reduction in ►► Recommended best practice based on the clinical experience of the exacerbations or symptoms. (Strong) guideline development group

GPPs (also see quick reference guide in online supplementary file on April 24, 2020 by guest. Protected 1) ►► Optimisation of other asthma therapies, including Declarations of interest establishing good adherence to inhaled therapies, All members of the GDG made declarations of interest in should be performed before considering a trial of line with BTS policy and further details can be obtained oral macrolide therapy. on request from BTS. Guideline Group members are ►► Referral to a respiratory specialist or specialist asthma listed in appendix 1 to the full guideline. service should be considered prior to initiation of macrolide therapy aimed at reducing exacerbation Stakeholder organisations frequency. Stakeholders were identified at the outset and were noti- ►► For safety purposes, an ECG should be performed fied when the guideline was available for public consul- prior to initiation of macrolide therapy to assess QTc tation. interval. If QTc is >450 ms for men and >470 ms for

Smith D, et al. BMJ Open Resp Res 2020;7:e000489. doi:10.1136/bmjresp-2019-000489 3 Open access BMJ Open Resp Res: first published as 10.1136/bmjresp-2019-000489 on 23 April 2020. Downloaded from

women then this is considered a contraindication to could be used to minimise side effect risk with initiating macrolide therapy. Baseline liver function subsequent titration according to clinical response tests (LFTs) should also be measured. (Conditional) ►► Patients should be counselled about potential adverse ►► When using macrolides to reduce exacerbation effects before starting therapy, including gastrointes- rates, therapy should be offered for a minimum of 6 tinal upset, hearing and balance disturbance, cardiac months. (Strong) effects and microbiological resistance. ►► Macrolides can be considered with the aim of ►► Microbiological screening of sputum before and improving quality of life but may require a long during macrolide therapy may be clinically helpful period of therapy (eg, 1 year) for significant effects. in patients who are able to expectorate sputum. This (Conditional) would allow monitoring for the development of resistance and detect changes in microbial growth to direct GPPs (also see quick reference guide in online supplementary file appropriate antibiotic therapy if required. However, 1 the resource implications of this approach have not been assessed. ►► Therapies should be optimised in accordance with ►► If oral macrolide therapy is considered, justification BTS Bronchiectasis Guidelines before considering for ongoing treatment should be guided by clin- long-term macrolide therapy (eg, airway clearance ical response based on specific outcome measures, techniques and attendance at pulmonary rehabilita- including exacerbation frequency, symptoms and tion courses). quality of life assessed at baseline. ►► Macrolides should only be started following discus- ►► A risk:benefit profile should be considered in sion and shared decision-making between the patient each individual if significant side effects from oral and a respiratory specialist. macrolide therapy develop. If gastrointestinal side ►► For safety purposes, an ECG should be performed effects occur at the higher dose of azithromycin prior to initiation of macrolide therapy to assess QTc (500 mg three times a week), a dose reduction to interval. If QTc is >450 ms for men and >470 ms for azithromycin 250 mg three times a week could be women then this is considered a contraindication to considered if macrolide therapy has been of clinical

initiating macrolide therapy. Baseline LFTs should copyright. benefit. also be measured. ►► Liver function tests should be checked one month ►► Patients should be counselled about potential adverse after starting treatment and then every 6 months. An effects before starting therapy, including gastrointes- ECG should be performed one month after starting tinal upset, hearing and balance disturbance, cardiac treatment to check for new QTc prolongation. If present, treatment should be stopped. effects and microbiological resistance. Microbio- ►► Symptom improvement with macrolide treatment logical assessment of sputum should be performed before therapy, including investigation for NTM.

may be minimal and not consistent across all people http://bmjopenrespres.bmj.com/ with asthma. If macrolide therapy is considered for Macrolide monotherapy should be avoided if an NTM symptom reduction, this should be for a defined is identified. When evaluating for NTM infection, period (6–12 months) and stopped if no symptomatic macrolides should not be used for 2 weeks before improvement is seen. Use of a validated symptom microbiological testing. score, such as the ACQ, may be useful to help to make ►► Accurate assessment of baseline exacerbation rate this assessment less subjective. should be determined before starting long-term ►► If the desired clinical outcome is achieved, the macrolides for bronchiectasis. possibility of breaks in therapy may be considered ►► Liver function tests should be checked one month to reduce the treatment burden for patients. It is after starting treatment and then every 6 months. unclear whether this may also reduce antimicrobial An ECG should be performed 1 month after starting on April 24, 2020 by guest. Protected resistance rates. treatment to check for new QTc prolongation. If present, treatment should be stopped. Bronchiectasis ►► Subsequent follow-up at 6 and 12 months should Recommendations determine whether benefit is being derived from ►► Long-term macrolide treatment could be offered to therapy. If there is no benefit, treatment should be reduce exacerbations in those with high exacerbation rates (ie, three or more per year). (Strong) stopped. ► ►► The dosing regimens with the greatest supportive ► Even if benefit is seen, consideration should be given evidence, when using macrolides to reduce exacer- to stopping treatment for a period each year, for bation rates, are azithromycin 500mg three times example over the summer. Such a drug holiday may a week, azithromycin 250mg daily, and erythro- help with reducing the development of resistance mycin ethylsuccinate 400mg twice a day. Astarting whilst maintaining efficacy because the vicious cycle dose of azithromycin 250mg three times a week has been broken.

4 Smith D, et al. BMJ Open Resp Res 2020;7:e000489. doi:10.1136/bmjresp-2019-000489 Open access BMJ Open Resp Res: first published as 10.1136/bmjresp-2019-000489 on 23 April 2020. Downloaded from

Chronic obstructive pulmonary disease therapy using objective measures, such as the exacer- Recommendations bation rate, CAT score or quality of life as measured ►► Long-term macrolide therapy could be considered by a validated assessment tool, such as SGRQ. If there for patients with COPD with more than three acute is no benefit, treatment should be stopped. exacerbations requiring steroid therapy and at least ►► It is not necessary to stop prophylactic azithromycin one exacerbation requiring hospital admission per during an acute exacerbation of COPD unless another year to reduce exacerbation rate. (Conditional) antibiotic with potential to affect the QT interval has ►► Long-term macrolide therapy could be considered also been prescribed. for a minimum of 6 months and up to 12 months to assess the impact on exacerbation rate. (Conditional) Bronchiolitis obliterans (including post-transplantation) Recommendations GPPs (also see quick reference guide in online supplementary file ►► Low-dose, long-term azithromycin (250 mg three 1 times a week) could be considered to prevent the ►► Non-pharmacological and pharmacological therapies occurrence of BOS post-lung transplantation. should be optimised prior to considering long-term (Conditional) macrolide therapy. This includes smoking cessa- ►► Low-dose azithromycin (250 mg alternate days for tion, optimised inhaler technique, optimised self- a trial period of 3 months) could be considered to management care plan, airway clearance techniques treat BOS occurring in lung transplant recipients. and attendance at pulmonary rehabilitation courses. (Conditional) ►► Macrolides should only be started following discus- sion and shared decision-making between the patient and a respiratory specialist. The use of macrolides in other respiratory ►► For safety purposes, an ECG should be performed conditions prior to initiation of macrolide therapy to assess QTc Cough interval. If QTc is >450 ms for men and >470 ms for Recommendations women then this is considered a contraindication to ►► Long- term macrolide antibiotics should not be used initiating macrolide therapy. Baseline LFTs should to manage patients with unexplained chronic cough. also be measured. (Conditional) copyright. ►► Patients should be counselled about potential adverse effects before starting therapy, including gastrointes- Organising pneumonia tinal upset, hearing and balance disturbance, cardiac There is insufficient evidence to make a recommenda- effects and microbiological resistance. tion. ►► Microbiological assessment of sputum should be performed before therapy, including investigation for

NTM. Macrolide monotherapy should be avoided if http://bmjopenrespres.bmj.com/ Safety issues an NTM is identified. Repeat assessments are recom- Gastro-intestinal effects mended with clinical decline or during exacerbations Good practice points to monitor resistance patterns. ►► Prior to initiating low-dose macrolide therapy, ►► Accurate assessment of baseline exacerbation rate patients should be warned of the possibility of gastro- should be determined before starting long-term intestinal side effects. macrolides for patients with COPD and a CT scan ►► Gastrointestinal side effects may be ameliorated by should be considered to exclude a possible diagnosis dose reduction, although this may also reduce clin- of bronchiectasis. ical efficacy. ►► A risk:benefit profile should be considered in ►► Clinicians should carefully consider the risk-to- benefit each individual if significant side effects from oral

balance when considering therapy for those with pre- on April 24, 2020 by guest. Protected macrolide therapy develop. If gastrointestinal side existing gastrointestinal symptomatology. effects occur at the higher dose of azithromycin (500 mg three times a week), a dose reduction to azithromycin 250 mg three times a week could be Cardiac effects considered if macrolide therapy has been of clinical Good practice points benefit. ►► Prior to initiating low-dose macrolide therapy, patients ►► Liver function tests should be checked one month should be asked if they have a history of heart disease, after starting treatment and then every 6 months. An previous low serum potassium measurements, a slow ECG should be performed one month after starting pulse rate, a family history of sudden death or known treatment to check for new QTc prolongation. If prolonged QT interval. Patients with such a history present, treatment should be stopped. should not receive low-dose macrolide therapy ►► Subsequent follow-up at 6 and 12 months should without careful consideration and counselling of the determine whether benefit is being derived from increased risk of adverse cardiac effects.

Smith D, et al. BMJ Open Resp Res 2020;7:e000489. doi:10.1136/bmjresp-2019-000489 5 Open access BMJ Open Resp Res: first published as 10.1136/bmjresp-2019-000489 on 23 April 2020. Downloaded from

►► Prior to initiating low-dose macrolide therapy, a drug disease should not preclude low-dose macrolide history looking for agents that might prolong the QTc monotherapy. interval should be sought (see appendices 3 and 4). ►► If there is any clinical suspicion of possible NTM Patients taking such agents should not receive low- disease, patients should be screened via examination dose macrolide therapy. of sputum samples prior to starting therapy. If posi- ►► Prior to initiating low-dose macrolide therapy, an tive for recognised potential pathogenic species, low- ECG should be performed to exclude a prolonged dose macrolide prophylaxis is contraindicated. QTc interval defined as >450 ms for men and >470 ms for women (see section √Methodology in appen- Disclaimer dices). Patients with a prolonged QTc interval should Healthcare providers need to use clinical judgement, not receive low-dose macrolides. knowledge and expertise when deciding whether it is ►► One month after initiating low-dose macrolide appropriate to apply recommendations for the manage- therapy, a second ECG should be performed to ment of patients. The recommendations presented here exclude the development of a prolonged QTc interval. are a guide and may not be appropriate for use in all Patients who develop a prolonged QTc interval on situations. The guidance provided does not override the low-dose macrolides should stop the macrolide. responsibility of healthcare professionals to make deci- ►► If any new drug that could potentially prolong QTc sions appropriate to the circumstances of each patient, time is started or if dose increases are made, repeat in consultation with the patient and/or their guardian ECG assessment. or carer.

Author affiliations Ototoxicity 1North Bristol Lung Centre, Southmead Hospital, Bristol, UK Good practice point 2Respiratory, Wye Valley NHS Trust, Hereford, UK ►► Prior to initiating low-dose macrolide therapy, 3Centre for Medical Education, Queens University Belfast, Regional patients should be asked if they have a history of Respiratory Centre, Belfast City Hospital, Belfast Health and Social Care Trust, hearing or balance difficulties. Such patients should Belfast, UK 4Medical Microbiology, Leeds Teaching Hospitals NHS Trust, Leeds, UK be made aware of the potential for a further, almost 5Cardiovascular and RespiratoryStudies, Hull York MedicalSchool/University always reversible, deterioration in hearing or balance of Hull, Hull, UK copyright. with macrolide therapy. Patients with pre-existing 6Institute of Biomedical and Clinical Science, College of Medicine & Health, hearing or balance difficulties who wish to proceed University of Exeter, Department of Respiratory Medicine, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK with treatment should be asked to report any change 7Oxford Respiratory Trials Unit, University of Oxford, Oxford NIHR Biomedical in hearing or balance promptly. Research Centre, Oxford, UK 8Pharmacy, University College London, London, UK

Other side effects Contributors DS and IDR chaired the Guideline Group, and as lead authors led the Good practice points drafting and revision of the document. All the authors drafted sections of the full http://bmjopenrespres.bmj.com/ guideline and undertook revisions of the paper. DS and IDR had final responsibility ►► Prior to initiating low-dose macrolide therapy, base- for the guideline and the summary paper submitted to BMJORR. line LFTs should be checked. Funding The authors have not declared a specific grant for this research from any ►► LFTs should be checked after one month of treat- funding agency in the public, commercial or not-for-profit sectors. ment and then every six months thereafter for the Competing interests CA, TC, IDR, PM, DS and RS had no funding to declare. SH duration of therapy. declared funding from Chiesi. NR declared funding from Rocket Medical, UK, Lung Therapeutics and BD. Patient consent for publication Not required. Antimicrobial resistance Provenance and peer review Commissioned; internally peer reviewed. Good practice points Data availability statement There are no data in this work.

►► The risks associated with increasing antimicrobial Open access This is an open access article distributed in accordance with the on April 24, 2020 by guest. Protected resistance should be discussed with patients prior to Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially , starting low-dose macrolide therapy. Patients should and license their derivative works on different terms, provided the original work is understand the risk that there may not be an effective properly cited, appropriate credit is given, any changes made indicated, and the antibiotic for them, or someone else, when needed in use is non-commercial. See: http://creativecommons.org/ licenses/by- nc/4. 0/. the future. ►► Prior to initiating low-dose macrolide monotherapy, patients should be asked if they have a history of References 1 Smith D, Rand D I, Addy CL, et al. BTS guideline for the use of long previous or current NTM infection or disease. term macrolides in adults with respiratory disease. Thorax 2020;75. Current NTM infection should be managed with 2 Smith D. BTS guideline on long term macrolides in adults with respiratory disease: not quite a panacea. Thorax 2020;75. reference to BTS guidance and precludes low-dose 3 Cystic fibrosis: long term azithromycin NICE, 2014. Available: https:// macrolide monotherapy. Successfully treated NTM www.nice.org.uk/advice/esuom37/chapter/full-evidence-summary

6 Smith D, et al. BMJ Open Resp Res 2020;7:e000489. doi:10.1136/bmjresp-2019-000489