HHE Respiratory 2019 | Page 22

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? 22 HHE 2019 | hospitalhealthcare.com