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 below 5
Close
communication
is required across
sectors to ensure
the safe ongoing
prescribing and
monitoring of
prophylactic
macrolides
Recommendations
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
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.
Recommendations
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.
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 to 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
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 monitoring 7 :
• 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?
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HHE 2019 | hospitalhealthcare.com