Key points from the evidence

The content of this evidence summary was up-to-date in November 2014. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.

Summary

Two randomised controlled trials (BAT: Altenburg J et al. 2013; n=89 and EMBRACE: Wong C et al. 2012; n=141) found that, compared with placebo, azithromycin reduced the rate of pulmonary exacerbations needing antibiotics in adults with non-cystic fibrosis bronchiectasis over 6 to 12 months. However, the evidence for other outcomes is unclear and the improvement in exacerbations must be balanced against the risk of experiencing adverse events and the development of antibiotic resistance.

Gastrointestinal adverse events occur very commonly with azithromycin treatment (incidence 1 in 10 or more). However, in the trials few people discontinued treatment due to adverse events. There is little published evidence to determine the efficacy and safety of azithromycin when used for non-cystic fibrosis bronchiectasis for more than 6 to 12 months.

Regulatory status: off-label. The topic was prioritised because there is uncertainty about the balance of risks and benefits when azithromycin is used long-term for non-cystic fibrosis bronchiectasis.

Effectiveness

  • In BAT and EMBRACE, azithromycin was statistically significantly better than placebo in reducing exacerbations needing antibiotics.

  • Azithromycin improved forced expired volume in 1 second (FEV1) statistically significantly more than placebo in BAT. However, there was no significant difference between the groups in changes in pre‑bronchodilator FEV1 in EMBRACE.

  • In BAT, St George's Respiratory Questionnaire (SGRQ) total scores improved statistically significantly more in the azithromycin group, compared with the placebo group. The difference was also clinically significant. However, in EMBRACE, there was no significant difference between the groups in change in SGRQ total score.

Safety

  • In BAT and EMBRACE, azithromycin was generally well‑tolerated and few people discontinued treatment due to adverse events.

  • The summary of product characteristics for Zithromax capsules reports that diarrhoea, abdominal pain, nausea and flatulence occur very commonly with azithromycin treatment (incidence 1 in 10 or more).

  • Azithromycin should be used with caution in people with a predisposition to QT interval prolongation.

  • Concerns have been raised over the emergence of macrolide resistance during long-term azithromycin treatment.

Patient factors

  • Children were not included in the BAT and EMBRACE trials. A study in 89 indigenous Australian, Maori and Pacific Island children with non-cystic fibrosis bronchiectasis found that azithromycin reduced the risk of exacerbations compared with placebo, but may not be applicable to the UK population.

  • The optimal dose, frequency and treatment duration is unclear. In BAT, azithromycin 250 mg daily was used for 12 months, compared with azithromycin 500 mg 3 times weekly for 6 months in EMBRACE.

Resource implications

According to the Drug Tariff (October 2014), excluding VAT, azithromycin costs:

  • £1.78 for 3 x 500 mg tablets

  • £1.97 for 4 x 250 mg tablets

  • £15.00 for 6 x 250 mg capsules

  • £4.06 for 15 ml, £6.10 for 22.5 ml or £11.04 for 30 ml x 200 mg/5 ml suspension.

Introduction and current guidance

Bronchiectasis is a permanent dilatation and thickening of the airways associated with chronic cough, sputum production, bacterial colonisation and recurrent infection (NICE Clinical knowledge summary: bronchiectasis).

NICE has not published a clinical guideline on non-cystic fibrosis bronchiectasis. The British Thoracic Society guideline for non-CF bronchiectasis, which has been accredited by NICE, advises that long-term oral or nebulised antibiotics should be considered in adults with non‑cystic fibrosis bronchiectasis who have 3 or more exacerbations per year that need antibiotic therapy, or who have fewer exacerbations that are causing significant morbidity. The antibiotic regimen should be determined by sputum microbiology. Similar advice is given for children.

The guideline notes that macrolide antibiotics may have disease-modifying activity and preliminary data suggest the need for a large randomised controlled trial. Since the guideline was published in 2010, randomised controlled trials on the use of macrolides for this condition have been published. This evidence summary considers the evidence for the safety and efficacy of long-term azithromycin in non-cystic fibrosis bronchiectasis.

Full text of Introduction and current guidance.

Product overview

Azithromycin is a macrolide antibiotic. In the UK, it is licensed for treating certain infections (bronchitis, community-acquired pneumonia, sinusitis, pharyngitis and tonsillitis, otitis media, skin and soft tissue infections and uncomplicated genital infections due to Chlamydia trachomatis) when they are known or likely to be due to one or more susceptible microorganisms (see summaries of product characteristics for azithromycin, for example, Zithromax capsules).

Although azithromycin is generally used for short courses only for its antibacterial properties, in common with some other macrolides, it also has anti-inflammatory properties. Therefore, it has been used for longer periods in chronic inflammatory conditions such as cystic fibrosis and non-cystic fibrosis bronchiectasis (Altenburg J et al. 2011). Use of azithromycin for non-cystic fibrosis bronchiectasis is off-label.

A NICE evidence summary on the off-label use of long-term azithromycin for cystic fibrosis is also available.

Consideration should be given to official guidance regarding the appropriate use of antibacterial agents. NICE is developing guidelines on Antimicrobial stewardship (expected March 2015) and Antimicrobial resistance – changing risk-related behaviours (expected March 2016).

Full text of Product overview.

Evidence review

  • This evidence summary is based on 2 randomised, double-blind, placebo-controlled trials that assessed the efficacy of long-term azithromycin for treating non-cystic fibrosis bronchiectasis, BAT (Altenburg J et al. 2013; n=89) and EMBRACE (Wong C et al. 2012; n=141).

  • Both trials included adults with confirmed non-cystic fibrosis bronchiectasis who had experienced pulmonary exacerbations requiring antibiotic treatment in the previous year (at least 3 in BAT and at least 1 in EMBRACE). In BAT, participants were randomised to receive azithromycin 250 mg daily or placebo for 12 months and, in EMBRACE, participants were randomised to receive azithromycin 500 mg 3 times weekly or placebo for 6 months. Participants in EMBRACE were followed for a further 6 months after the trial ended.

  • In BAT, statistically significantly fewer people taking azithromycin had at least 1 exacerbation needing antibiotic treatment over 12 months, compared with people taking placebo (46.5% compared with 80.0% respectively; absolute risk reduction 33.5%, 95% confidence interval [CI] 14.1% to 52.9%; p value not reported). Three people would need to be treated with azithromycin for 12 months to maintain clinical stability in 1 person.

  • In EMBRACE, in the 6-month treatment period, the rate of exacerbations needing antibiotics was statistically significantly lower with azithromycin compared with placebo (0.59 per patient compared with1.57 per patient respectively; relative risk [RR] 0.38, 95% CI 0.26 to 0.54; p<0.0001). The benefits persisted for a further 6 months without treatment.

  • A statistically significant improvement in percent of predicted FEV1 of 4.52% was seen at 12 months in the azithromycin group in BAT, compared with the placebo group (p=0.047). Changes in pre-bronchodilator FEV1 from baseline to 6 and 12 months did not differ significantly between the groups in EMBRACE.

  • In BAT, the improvement in SGRQ total scores was both statistically and clinically significant in the azithromycin group, compared with the placebo group (p=0.046). The mean change in SGRQ total score at 6 and 12 months did not differ significantly between azithromycin and placebo in EMBRACE.

  • In BAT, 42% of people in both the azithromycin and placebo groups experienced an adverse event. In EMBRACE, 83% of people taking azithromycin and 93% of people taking placebo experienced an adverse event. One person in BAT and 2 people in EMBRACE discontinued azithromycin treatment due to a suspected adverse event. Overall, azithromycin was reported to be generally well tolerated.

  • The summary of product characteristics for Zithromax capsules reports that diarrhoea, abdominal pain, nausea and flatulence occur very commonly with azithromycin treatment (incidence 1 in 10 or more). In common with other macrolides, azithromycin should be used with caution in people with a predisposition to QT interval prolongation (including electrolyte disturbances and concomitant use of drugs that prolong the QT interval). Reversible hearing loss can occur after long-term therapy with azithromycin (British national formulary, October 2014).

  • Development of macrolide resistance was reported in both studies. However, the clinical implications of macrolide resistance are unclear.

  • There is concern that long-term use of azithromycin in individuals with occult or active nontuberculous mycobacteria infection could lead to resistance, which might complicate its treatment (US Cystic fibrosis pulmonary guidelines, 2013). Specialists involved in the production of this evidence summary have suggested that people with non-cystic fibrosis bronchiectasis who are selected for long-term azithromycin treatment should be screened for nontuberculous mycobacterial infection.

  • Both trials were placebo-controlled. The numbers of patients included in the trials were small, meaning that analysis of some outcomes may have been underpowered. In BAT, azithromycin 250 mg daily was used for 12 months, whereas azithromycin 500 mg 3 times weekly for 6 months (plus 6 months follow-up) was used in EMBRACE. These differences mean the optimal dose, frequency and treatment duration of azithromycin is unclear. Also, there is little published evidence to determine the efficacy and safety of azithromycin when used for non-cystic fibrosis bronchiectasis for more than 6 to 12 months. Both trials included adults only from non-UK populations (the Netherlands and New Zealand) and the results may not be generalisable to children with non-cystic fibrosis bronchiectasis.

  • A randomised controlled trial (Valery PC et al. 2013) has compared azithromycin (30 mg/kg weekly, maximum 600 mg) and placebo in indigenous Australian, Maori and Pacific Island children (n=89; mean age 4 years) with non-cystic fibrosis bronchiectasis. Over a mean of 20.7 months, children taking azithromycin were statistically significantly less likely to have pulmonary exacerbations than those taking placebo (RR 0.50, 95% CI 0.35 to 0.71; p<0.0001). However, the results of this study may not be applicable to the children in the UK. No children or young people aged over 8 years were included in the study.

  • The trials show that long-term azithromycin reduces exacerbations in the short term compared with placebo, but the evidence for other outcomes is unclear. The improvement in exacerbations must be balanced against the risk of experiencing adverse events and the development of macrolide-resistance.

Full text of Evidence review.

Context and estimated impact for the NHS

Costs of 6 months' treatment with azithromycin 250 mg daily are £89.63 for tablets, £455.00 for capsules and between £369.46 and £507.84 for suspension (Drug Tariff, October 2014).

Costs of 6 months' treatment with azithromycin 500 mg 3 times weekly are £46.28 or £76.83 for tablets, £390.00 for capsules and between £316.68 and £475.80 for suspension (Drug Tariff, October 2014).

Full text of Context and estimated impact for the NHS.

Information for the public

A plain English summary is available on the NICE website. This sets out the main points from the evidence summary in non-technical language and may be especially helpful for people with non-cystic fibrosis bronchiectasis who are thinking about trying long-term azithromycin.

About this evidence summary

'Evidence summaries: unlicensed or off-label medicines' summarise the published evidence for selected unlicensed or off-label medicines that are considered to be of significance to the NHS, where there are no clinically appropriate licensed alternatives. The summaries provide information for clinicians and patients to inform their decision‑making and support the construction and updating of local formularies.

The summaries support decision-making on the use of an unlicensed or off-label medicine for an individual patient, where there are good clinical reasons for its use, usually when there is no licensed medicine for the condition requiring treatment, or the licensed medicine is not appropriate for that individual.

The strengths and weaknesses of the relevant evidence are critically reviewed within this summary, but this summary is not NICE guidance.