Key recommendations for the use of macrolide antibiotics in respiratory disease

The British Thoracic Society (BTS) are due to publish guidance later this year on the long-term use of macrolide antibiotics in respiratory disease. These new guidelines will provide much needed advice in the use of macrolides as immunomodulatory agents across various respiratory disease areas. 

The guideline will be applicable to adult patients only, and some therapeutic areas will not be covered such as the use of macrolides in cystic fibrosis, long term use for chronic rhinosinusitis, and the treatment of respiratory infection.  

This article outlines key recommendations and implications for practitioners.

Recommendations

At the time of the development of the guideline, no macrolide antibiotics were licenced in the UK for long-term low-dose usage as immunomodulatory agents. Healthcare providers should use clinical judgement, knowledge and expertise when deciding whether it is appropriate to apply these recommendations for the management of their patients, considering individual patient needs and choice. The recommendations are a guide and may not be appropriate for use in all situations.

• Asthma
  Oral macrolide therapy should be considered to reduce exacerbation frequency in adults aged 50 to 70 years of age with ongoing symptoms despite more than 80 percent adherence to high dose inhaled steroids (>800mcg/day) and at least one exacerbation requiring oral steroids in the past year. 
  This recommendation reflects the population within the AMAZES randomised controlled trial which represents the highest quality evidence of macrolide therapy leading to a significant reduction in exacerbations. Treat for six to twelve months duration, at 500mg three times a week.
• COPD
  Long term macrolide therapy should be offered to patients with COPD who are non-smokers, with three or more acute exacerbations requiring steroid therapyand/or one exacerbation requiring hospital admission per year to reduce exacerbation rate. Therapy should be considered for a minimum of six monthsand considered for a 12 month period to assess exacerbation rate. The recommendation threshold slightly differs to that in the NICE COPD 2018 guidelines.
• Bronchiectasis
  Long term macrolide treatment should be considered to reduce exacerbations in those with high exacerbation rates (i.e. 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 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:
• Low dose, long term azithromycin (250 mg thrice weekly) 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
• Avoid use in current smokers as macrolides have shown to be ineffective
• There was insufficient evidence to make a recommendation regarding use in Organising pneumonia
• The decision was made notto conduct a comprehensive evidence-based review and develop specific recommendations regarding the role of macrolides in managing diffuse pan bronchiolitis.

Potential adverse effects which require monitoring 
(see electronic Medicines Compendium and the BNF for more details)

• Gastrointestinal (nausea, vomiting, pain, diarrhoea)
• Liver dysfunction
• Ototoxicity: Requires regular audiology testing
• Cardiac – QT interval prolongation: Requires electrocardiogram before and during therapy
• Possible antimicrobial resistance (microbiome effect)

Implementation of guidance

• The BTS macrolide guidelines should be used in conjunction with the relevant disease guideline (such as the BTS Guideline for Bronchiectasis). 
• Holistic care (both pharmacological and non-pharmacological) should be optimised first, ensuring that patients are being treated appropriately to their disease stage and severity, and that individual circumstances have been considered. This includes co-morbidities, polypharmacy, addressing non-adherence and ensuring smoking cessation before considering macrolides.
• Prior to macrolide initiation, in-depth patient consultation and counselling are required to balance risks and benefits, discuss side effects, 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. If taking as a coated tablet, they must be swallowed whole and not chewed or crushed.
• Electrolyte disturbances and medicines such as amiodarone, fluoroquinolones and some antidepressants or antipsychotics may potentiate QT prolongation.

Practical considerations

• The guideline will be published with an example of an associated generic patient information leaflet which can be locally adapted and will include the basic information to cover during counselling. Close communication will be necessary across primary, secondary and tertiary care to ensure clear shared care and that follow up plans are developed and followed, ensuring that prescribing and monitoring are ongoing.  
• Close liaison with the healthcare team (particularly pharmacists) is also necessary to ensure recognition of adverse effects (especially during an exacerbation where acute therapies may interact) and manifestation of any medicine interactions. This is especially important during the initial phase after starting therapy where patients may present to primary care providers or acute services.
• Increased discussion and rapport with patients will support the increased pharmacovigilance required and for potential MHRA Yellow Card reporting. Antimicrobial stewardship is also necessary.