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), BNF for children (BNFc) or the MHRA or NICE websites for up-to-date information.

Summary

A Cochrane review (10 studies, n=959) assessed the use of long-term azithromycin for cystic fibrosis. Six studies (n=836) had a low risk of bias. Various dosing regimens were used, the most common being 250−500 mg 3 times weekly. In 4 studies (n=549), treatment with azithromycin statistically significantly improved forced expired volume in 1 second (FEV1; the primary outcome) over 6 months compared with placebo. Azithromycin doubled the rate of being free of exacerbations over 6 months compared with placebo; however, the data were heterogeneous and should be interpreted with caution. The need for oral antibiotics was statistically significantly reduced with azithromycin, but there were limited data on the need for intravenous antibiotics and other secondary outcomes. Adverse events were uncommon and not obviously associated with azithromycin. There is little published evidence to determine the safety of azithromycin when used for over 6 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 cystic fibrosis.

Effectiveness

In the Cochrane review, compared with placebo, azithromycin statistically significantly:

  • improved FEV1 (the primary outcome) over 6 months compared with placebo (4 studies, n=549; mean difference 3.97% of predicted, 95% confidence interval [CI] 1.74 to 6.19).

  • improved the rate of being free from exacerbations over 6 months (4 studies, n=609; odds ratio [OR] 1.96, 95% CI 1.15 to 3.33). However, the data were heterogeneous and should be interpreted with caution.

  • reduced the need for oral antibiotics (3 studies, n=527; OR 0.28, 95% CI 0.19 to 0.42). However, there were limited data on the need for intravenous antibiotics and other secondary outcomes.

Safety

  • In the Cochrane review, adverse events were uncommon and not obviously associated with azithromycin. Over 2−12 months, no serious adverse events were reported and study withdrawals were rare.

  • The summary of product characteristics for Zithromax capsules reports that, whilst azithromycin is generally well tolerated, 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 (particularly Staphylococcus aureus) during long-term azithromycin treatment.

Patient factors

  • In the RCTs in the Cochrane review, no clear effect was found on patient-reported quality of life with azithromycin.

  • No children aged under 6 years were included in the studies in the Cochrane review.

  • Azithromycin is taken orally. Some people may prefer oral to inhaled antibiotic treatment.

  • The most common dosing frequency used in studies in the Cochrane review was 250−500 mg 3 times weekly; the optimum dosing regimen is unclear.

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.

Based on guidance from the Cystic Fibrosis Trust, depending on the formulation used, the cost (excluding VAT) of 6 months' treatment with azithromycin ranges from:

  • £46.28 to £430.56 in adults (500 mg 3 times weekly)

  • £38.41 to £220.80 in children and young people weighing 15−40 kg (250 mg 3 times weekly).

Introduction and current guidance

The lungs of people with cystic fibrosis can become infected by bacteria (most commonly Pseudomonas aeruginosa). Recurrent, intermittent infection of the airways occurs and, if bacterial infection is not controlled, chronic infection can develop, which may accelerate declining lung function, respiratory failure and death. The length and quality of life for people with cystic fibrosis is thought to be strongly influenced by the success or failure to eradicate P. aeruginosa in early childhood and by subsequent antibiotic treatment of respiratory infective exacerbations.

The guideline on antibiotic treatment for cystic fibrosis from the Cystic Fibrosis Trust (2009) advises that a 6 month trial of oral azithromycin should be considered in people with cystic fibrosis who are deteriorating on conventional therapy, irrespective of their infection status. However, not all patients will benefit from this therapy.

This evidence summary considers the evidence to support the off-label use of long-term azithromycin for treating people with cystic fibrosis. For the purpose of this evidence summary, long-term is defined as 6 months or more, as recommended by the Cystic Fibrosis Trust guideline.

A NICE clinical guideline on diagnosis and management of cystic fibrosis is in development. The expected date of publication is February 2017.

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

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). Use of azithromycin for cystic fibrosis is off-label.

Although they are active against some other pathogens seen in people with cystic fibrosis, macrolides such as azithromycin have no direct bactericidal activity against P. aeruginosa. The Cystic Fibrosis Trust Guideline on antibiotic treatment for cystic fibrosis notes that the mode of action of macrolides in cystic fibrosis is unknown. Possible mechanisms may involve an anti-inflammatory action, and interference with the protective biofilm of P. aeruginosa and the adherence of P. aeruginosa to epithelial cells.

If a 6 month trial of azithromycin is considered necessary, the Cystic Fibrosis Trust guideline recommends that the dose is generally 250−500 mg 3 times weekly, depending on the person's weight.

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

Full text of Product overview.

Evidence review

This evidence review is based on a Cochrane review that examined the use of macrolide antibiotics for treating cystic fibrosis (Southern KW et al. 2012).

  • The Cochrane review (8 randomised controlled trials and 2 crossover studies: n=17 to 260) included 959 adults and children with confirmed cystic fibrosis. Eight of the included studies compared azithromycin with placebo; 1 compared high- and low-dose azithromycin; and 1 compared once weekly and once daily dosing regimens. Four of the studies (n=544) comparing azithromycin with placebo used a 250−500 mg 3 times weekly dosage. Treatment duration ranged from 2−12 months.

  • Meta-analysis of 4 studies (n=549) found that azithromycin statistically significantly improved FEV1 (the primary outcome) over 6 months compared with placebo (mean difference 3.97% of predicted, 95% CI 1.74 to 6.19). The authors state that this is likely to be of clinical significance in people with cystic fibrosis. Beyond 6 months, the benefits of azithromycin treatment on FEV1 are less clear because they are based on 1 small study only (n=82).

  • At 6 months, people treated with azithromycin were about twice as likely to be free of exacerbations as people treated with placebo (4 studies, n=609; OR 1.96, 95% CI 1.15 to 3.33). However, the data were heterogeneous and should be interpreted with caution.

  • In 3 studies (n=527), treatment with azithromycin was associated with a statistically significant reduction in the need for oral antibiotics (OR 0.28, 95% CI 0.19 to 0.42). However, the data were limited for intravenous antibiotics. See the evidence review section of this evidence summary for more information.

  • People taking azithromycin gained statistically significantly more weight than those taking placebo (2 studies, n=445; mean difference 0.62 kg, 95% CI 0.26 kg to 0.98 kg).

  • No clear effect was seen with azithromycin treatment on patient-reported quality of life.

  • Meta-analysis of 2 studies (n=445) found no statistically significant difference between the groups in rates of admission to hospital.

  • There is little information on the long-term safety of azithromycin treatment for cystic fibrosis. No serious adverse events were reported in the studies included in the Cochrane review with azithromycin use for 2−12 months. In studies comparing azithromycin with placebo, study withdrawals were reportedly rare and not obviously associated with azithromycin.

  • The summary of product characteristics for Zithromax capsules reports that, whilst azithromycin is generally well tolerated, diarrhoea, abdominal pain, nausea and flatulence occur very commonly with azithromycin treatment (incidence 1 in 10 or more). Common adverse effects (incidence between 1 in 10 and 1 in 100) include anorexia, vomiting, dyspepsia, dizziness, headache, paraesthesia, dysgeusia (abnormal taste), visual impairment, deafness, pruritus, rash, arthralgia, and fatigue. 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 with long-term therapy with azithromycin (British national formulary, September 2014).

  • No children aged under 6 years were included in the studies in the Cochrane review. Various dosing regimens were used, the most common being 250−500 mg 3 times weekly. In the key meta-analyses discussed in this evidence summary (including lung function, pulmonary exacerbations, need for antibiotics and hospitalisation), more than 90% of participants used this dosing regimen. There is little published evidence to determine the efficacy and safety of azithromycin when used for cystic fibrosis in other dosing regimens or for more than 6 months.

  • Concerns have been raised over the emergence of macrolide resistance (particularly Staphylococcus aureus) during long-term azithromycin treatment. The US Cystic fibrosis pulmonary guidelines (2013) state that long-term use of azithromycin in individuals with occult or active nontuberculous mycobacteria infection could lead to resistance, which might complicate its treatment. Therefore, the guideline suggests that patients should be screened for nontuberculous mycobacteria before azithromycin is initiated, and reassessed periodically at 6- to 12-month intervals. Azithromycin monotherapy should not be used in patients infected with nontuberculous mycobacteria.

Full text of Evidence review.

Context and estimated impact for the NHS

Depending on the formulation used, costs (excluding VAT) of 6 months' treatment with azithromycin based on regimens included in the Cystic Fibrosis Trust Guideline on antibiotic treatment for cystic fibrosis are as follows:

  • Adult (500 mg 3 times weekly): £46.28 to £390.00 for tablets or capsules and £316.68 to £430.56 for suspension.

  • Child or young person weighing 15−40 kg (250 mg 3 times weekly): £38.41for tablets, £195.00 for capsules and £158.34 to £220.80 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 or parents of children with cystic fibrosis who are considering starting 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.