Long-term macrolides in respiratory care

The British Thoracic Society will soon publish its guidance on the long-term use of macrolide antibiotics in respiratory disease. This article outlines the recommendations, evidence base and implications for practitioners

The British Thoracic Society (BTS) macrolide guideline is the first of its kind dedicated solely to the use of oral macrolides, long term, in respiratory disease (where ‘long term’ refers to any duration longer than that used to treat an exacerbation). The dosing is ‘low dose’, that is, doses that are not used to ‘treat’ an acute exacerbation and are essentially prophylactic.

Macrolides are bacteriostatic antibiotics characterised by their large lactone ring structures with a broad spectrum of activity against many gram-positive bacteria. They were discovered in the 1950s when erythromycin was isolated from the soil bacterium Streptomyces erythraeus. In the 1970s and ‘80s, synthetic derivatives of erythromycin, including clarithromycin and azithromycin, were developed.

Mode of action

Macrolide antibiotics act by inhibiting protein synthesis of bacteria by binding to the 50S ribosomal element. Resistance occurs by several mechanisms. Clarithromycin and azithromycin are more active than erythromycin against several gram-negative bacteria as well as Mycoplasma pneumonia, Helicobacter pylori, Toxoplasma gondii, cryptosporidia and several atypical mycobacteria.¹

Developing the guideline

Many studies were reviewed during the guideline development process and these used various different macrolide agents (predominantly clarithromycin and azithromycin). However, the greatest volume and best available evidence is related to the use of azithromycin, hence the recommendations made throughout the BTS guidance relate to azithromycin.

The guideline is applicable to adult patients and has some exclusions:

• Paediatric practice excluded 
• Use of macrolides in cystic fibrosis (CF) has not been included-recognising the parallel work of the National Institute for Health and Care Excellence in this area² 
• Long-term macrolides for chronic rhinosinusitis have not been included
• The use of macrolides as antibacterial agents to treat respiratory infection is excluded.

Disease areas covered by guideline are:

• Asthma
• Chronic obstructive pulmonary disease (COPD)
• Bronchiectasis
• Bronchiolitis obliterans (including post-transplantation)
• ‘Other’ conditions (chronic cough, organising pneumonia, diffuse pan bronchiolitis (DPB)).

At the time of guideline development, no macrolide antibiotics are licenced in the UK for long-term, low-dose usage as immunomodulatory agents. Healthcare providers need to use clinical judgment, knowledge and expertise when deciding whether it is appropriate to apply recommendations for the management of patients. The recommendations cited are a guide and might not be appropriate for use in all situations. The guidance provided does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of each patient, in consultation with the patient and/or their guardian or carer.³ It is envisaged that initiation of macrolides will occur in a secondary or tertiary care setting.

Asthma 

The evidence reviewed for macrolide use in asthma presented some issues; for example, there was great heterogeneity of study designs, many were of a small size or underpowered. Studies ranged in duration from 6–12 months and some used exacerbations as a primary outcome and with varying definitions of what constituted an exacerbation; other studies used this as a secondary outcome measure. Hence there was some limit to applicability of evidence to the wider asthma population. 

There were two large trials upon which the recommendations for azithromycin use were based: the AMAZES and AZIZAST trials (both studies also had slightly differing definitions of an exacerbation).

• AMAZES was specifically designed to determine a reduction in exacerbation frequency in response to azithromycin. It was a 48-week study using 500mg thrice weekly. It demonstrated a significant reduction in exacerbations (p<0.0001) but the AZIZAST trial did not (p=0.68). This might reflect the duration of treatment, dose effect or differing study populations (larger population in AMAZES (n=420) on high-dose inhaled steroids with an average of one exacerbation in previous year). Both those with eosinophilic asthma and non-eosinophilic asthma demonstrated a reduction in exacerbations, with a slightly greater reduction seen in the eosinophilic group.⁴
• AZISAST was a six-month study using 250mg thrice weekly (lower dose and smaller population (n=109) than AMAZES) with higher inhaled steroid doses and two exacerbations in the previous year. There was no significant difference in exacerbation rates compared with placebo. Patients from 18 to 75 years were eligible for entry to study.

Overall there was a clear reduction in asthma exacerbations (both moderate and severe). This was seen for both eosinophilic and non-eosinophilic exacerbations with a greater reduction seen in eosinophilic groups.

The majority of studies demonstrated improvement in asthma symptoms. Actual changes were minimal and unlikely to be of clinical significance (statistical significance was reached in only three studies).

Azithromycin use may reduce bronchial hyper-responsiveness in asthma and might result in a reduction in oral steroid dose, but this is not a consistent finding. It can result in a small improvement in lung function and peak expiratory flow rate; it may also result in measurable improvements in quality of life (QoL) but the clinical impact of these changes remains unknown and may be very small.

There is no evidence of the impact of macrolide therapy on mortality, exercise capacity, disease progression or sputum production in people with asthma, therefore no recommendations in regard to these outcomes can be made in this guideline.

Recommendation 

Oral macrolide therapy should be considered to reduce exacerbation frequency in adults (50–70 years), with ongoing symptoms despite >80% adherence to high-dose inhaled steroids (>800mcg/day beclomethasone diproprionate equivalent) and at least one exacerbation requiring oral steroids in the past year. This recommendation reflects the population within the AMAZES⁴ randomised, controlled trial (RCT), which represents the highest quality evidence of macrolide therapy leading to a significant reduction in exacerbations. Treat for 6–12 months’ duration, 500mg three-times a week.

COPD 

There were nine RCTs reviewed, ranging from 3 to 12 months’ duration and using different macrolides. The mean ages of participants were 64–72 years. There was no evidence of improvement in lung function and no mortality benefit. There was a statistically significant improvement in QoL measured by the St George’s Respiratory Questionnaire (SGRQ), but not clinically significant four-unit improvement as minimum clinically important difference. The number of hospitalisations was not significantly reduced in patients receiving long term macrolide therapy.

• Long term macrolide antibiotics are effective in reducing the acute exacerbation rate in patients with COPD with high exacerbation rates (that is, three or more exacerbations per year)
• Treatment for less than six months with macrolide therapy demonstrates limited benefit in reducing exacerbations. Treatment courses of 12 months demonstrated the biggest effect size in reduction of exacerbation rate
• Subgroup analysis of the largest trial of COPD: precise findings are that there is no significant benefit of macrolide in GOLD stage 4 patients, current smokers and those age 65 or below⁵ 

Recommendation 

Long-term macrolide therapy should be offered to patients with COPD who are non-smokers, with three or more acute exacerbations requiring steroid therapy and/or one exacerbation requiring hospital admission per year to reduce exacerbation rate (strong).

• Long-term macrolide therapy should be considered for a minimum of six months and considered for a 12-month period to assess exacerbation rate.

Note – this differs slightly to the recommendations in the recent NICE COPD 2018 guidance,⁶ which states: ‘Consider azithromycin (usually 250mg three-times a week) for people with COPD if they:

• do not smoke, and
• have optimised non-pharmacological management and inhaled therapies, relevant vaccinations and (if appropriate) have been referred for pulmonary rehabilitation, and
• continue to have one or more of the following, particularly if they have significant daily sputum production:
  • frequent (typically four or more per year) exacerbations with sputum production 
  • prolonged exacerbations with sputum production
  • exacerbations resulting in hospitalisation’.⁶

Bronchiectasis

There were three main RCTs that were the basis of recommendations (BAT, BLESS and EMBRACE). They all studied use of a macrolide versus placebo in bronchiectasis. Studies ranged from 6–12 months’ duration and had different entry criteria. Mean ages of participants were 60–62 years.

The studies showed a reduction in the number of exacerbations and some symptom improvement. 

Long-term macrolide therapy may reduce sputum volume and weight. There was some sputum reduction but the impact of this to patients was unclear and there was no impact on exercise capacity. 

There was little change in QoL but there is evidence of an improvement in QoL measured by the SGRQ when azithromycin 250mg daily is used for one year. 

Dosing regimens with greatest supportive evidence for exacerbation reduction are azithromycin 250mg OD, azithromycin 500mg three-times a week and erythromycin ethylsuccinate 400mg BD. 

Studies with other dosing regimens, including azithromycin 250mg three-times a week (as pragmatically suggested in the BTS bronchiectasis guideline) have also reported reduction in exacerbations but have a lower evidence base. 

Studies with greatest evidence for reduction in exacerbations used therapy for a minimum of six months; the impact beyond one year is unknown. There is evidence for reduction in exacerbations over a 12-month period when therapy is used for six months and then not for the subsequent six months but the impact of subsequently recommencing is unknown. 

Recommendation 

Long-term macrolide treatment should be considered to reduce exacerbations in those with high exacerbation rates (that is, three or more per year). Therapy should be for a minimum of six months. The impact beyond 12 months is unknown. The dosing regimens with the greatest supportive evidence, when using macrolides to reduce exacerbation rates, are azithromycin 250mg daily, azithromycin 500mg three times a week and erythromycin ethylsuccinate 400mg twice a day. However, a starting dose of 250mg three-times a week can be used to minimise side effect risk with subsequent titration according to clinical response.

Bronchiolitis obliterans

The overall quality of the evidence is at best modest in this area. Bronchiolitis obliterans syndrome (BOS) is a devastating complication of lung transplantation, hence any intervention offering the chance of prevention, reversal or stabilisation is welcome. Long-term macrolide use is a low-risk intervention. On this basis, two low evidence recommendations have been made.

Recommendations

• Low-dose, long-term azithromycin (250mg three-times a week) can be used to prevent the occurrence of BOS post-lung transplantation 
• Low-dose azithromycin (250mg alternate days for a trial period of three months) can be used to treat BOS occurring in lung transplant recipients. 

Recommendations against macrolide use

• Long-term macrolide antibiotics should not be used to manage patients with unexplained chronic cough 
• Organising pneumonia – There is insufficient evidence to make a recommendation.
• The BTS felt that is was not warranted to conduct a comprehensive evidence-based review and develop specific recommendations regarding the role of macrolides in managing DPB.
• Avoid use in current smokers as macrolides have shown to be ineffective. 

Potential adverse effects requiring monitoring⁷: 

• Ototoxicity – regular audiology testing
• Cardiac – QT interval prolongation – electrocardiogram required before and during therapy
• Gastrointestinal (nausea, vomiting, pain, diarrhoea)
• Liver dysfunction
• Antimicrobial resistance/microbiome effect?

(Note: This is not an exhaustive list – consult the BNF or Summary of Product Characteristics for more in-depth information on adverse effects).

Implementation of guidance

The BTS macrolide guidelines should be used in conjunction with the relevant disease guideline (for example, with BTS bronchiectasis guide). Holistic care (both pharmacological and non-pharmacological) should be optimised first, ensuring that patients are being treated appropriate to disease stage/severity and that individual circumstances have been taken into account. This includes comorbidities, polypharmacy, addressing non-adherence, and ensuring smoking cessation before considering macrolides.

Prior to macrolide initiation, in-depth patient consultation and counselling are required to present treatment risks and benefits, discuss side effects, review potential or actual interactions (especially during exacerbation) and to manage expectations of therapy. 

Azithromycin is principally cleared by the liver so should be used with caution in significant liver disease. It can be taken with or without food at any time of day but indigestion remedies should be avoided for two hours before the azithromycin dose and if taking as a coated tablet, must be swallowed whole not chewed or crushed.

Electrolyte disturbances and medicines such as amiodarone, fluoroquinolones and some antidepressants/antipsychotics may potentiate
QT prolongation.⁷

Practical considerations

The guideline will be published with an associated generic patient information leaflet that can be locally adapted and which will include the basic information to cover during counselling.

Close communication will be necessary across primary, secondary/tertiary care to ensure clear shared care and follow up plans are developed and followed, ensuring that prescribing and monitoring are ongoing. Close liaison with the healthcare team (in particular with pharmacists) is also necessary to ensure recognition of adverse effects and manifestation of any medicine interactions (recognition more so during an exacerbation where acute therapies may interact). This is especially important during the initial phase after starting therapy when patients may present to primary care providers or acute services.

Increased discussion and rapport with patients will support the increased pharmacovigilance required and also for potential Medicines and Healthcare products Regulatory Authority ‘Yellow card’ reporting. Antimicrobial stewardship is also necessary.

What we do not know

The use of macrolides during disease exacerbation is unclear and evidence for this is lacking. It may be appropriate to hold the macrolide during exacerbation, for example, in bronchiectasis where the patient may require intravenous antibiotics. Some experts believe that patients should not be treated with full dose macrolide during an exacerbation if on prophylaxis, however some clinicians acutely increase the dose of the same agent. Current practice varies widely across the UK.

Limitations of the available macrolide evidence mean we do not have any data on long term effect, not only in terms of safety and clinical effect but also antimicrobial resistance and the microbiome. There is no long-term data on use beyond one year or head-to-head comparison between the different macrolides to show superiority of one over another.

The guidelines raise relevant research questions such as: which disease phenotypes/subgroups would gain most benefit from macrolides? Is seasonal use of macrolides or rotation with other antibiotics beneficial? What is the potential for use in a younger population (study populations were older)? Also, is the threshold for use that has been suggested appropriate? Would this need to be tightened or relaxed? Further research will inform these questions.

Conclusions 

The new BTS macrolide guidelines will provide much needed guidance for the use of macrolides as immunomodulatory agents across various respiratory disease areas. However, guidelines are a guide and common sense applies – practitioners should ‘use clinical judgment, knowledge and expertise’ before initiation, taking into account individual patient needs and choice.

Macrolides appear to reduce inflammation, bronchial hyperreactivity and exacerbations and may affect other parameters too. They are not a magic bullet – all other treatments should be optimised first and they should be avoided in current smokers (ineffective).

References

1. National Institutes of Health. Drug Record. Macrolide antibiotics. https://livertox.nih.gov/MacrolideAntibiotics.htm (accessed August 2019).
2. National Institute for Health and Care Excellence. Cystic fibrosis: long-term azithromycin. Evidence summary ESOUM37. www.nice.org.uk/advice/esuom37/chapter/Key-points-from-the-evidence (accessed August 2019).
3. British Thoracic Society. Long-term macrolide guideline 2019. www.brit-thoracic.org.uk/quality-improvement/guidelines/long-term-macrolide-use/ (accessed August 2019).
4. Gibson PG et al. Effects of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES) a randomised, double blind, placebo- controlled trial. Lancet. 2017;390(10095):659–68.
5. Albert RK et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med 2011;365:689–98.
6. National Institute for Health and Care Excellence. NG115. Chronic obstructive pulmonary disease in over 16s: diagnosis and management. December 2018 www.nice.org.uk/guidance/ng115 (accessed August 2019).
7. British National Formulary https://bnf.nice.org.uk/ (accessed August 2019).