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
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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