HHE Respiratory 2019 | Page 20

RESPIRATORY 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 Ravijyot Saggu BPharm MRPharmS Clin Dip IP Senior Clinical Pharmacist, University College Hospital, London, UK 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 area 2 • 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 20 HHE 2019 | hospitalhealthcare.com • 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 licensed 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