Azithromycin – for better or worse in chronic lung infection? Professor Emma Baker Professor of Clinical Pharmacology St George's, University of London

Learning outcomes To consider whether/when long term azithromycin should be used in patients with COPD

Mr AZ 78 year old man –58 pack year smoking history –Short of breath on minimal exertion –CAT score 32 –Exacerbations every 6 weeks treated with antibiotics and steroids –FEV 1 32% predicted, FEV 1 :FVC 41% Who would offer this patient long term azithromycin to prevent exacerbations? Dose?

Additional history... He has stopped smoking and done pulmonary rehab His treatment is salbutamol, seretide and tiotropium Comorbidities include diabetes mellitus, ischaemic heart disease and osteoporosis He needs glasses, walks with a frame and uses a hearing aid CT scan shows bronchiectasis and emphysema, sputum cultures not done

Details Inclusion criteria –>40 years –>10 pack year smoking history –Post-bronchodilator FEV1 <80%, FEV1:FVC <70% –At least one course of systemic steroids/ emergency room visit/ hospitalisation for exacerbations in previous 6 months OR LTOT –Stable for preceding 4 weeks

Azithromycin 250mg daily

Outcome measures Primary –Time to first exacerbation Secondary –Quality of life –Nasopharyngeal bacterial colonisation –Adherence to study drug

Azithromycin and exacerbations 266 (1.48/year) 174 (1.83/year) NNT to prevent one exacerbation = 2.86

Having AECOPD per patient/year Age Gender FEV 1 Smoking status Study centre

He has stopped smoking and done pulmonary rehab His treatment is salbutamol, seretide and tiotropium

Comorbidities include diabetes mellitus, ischaemic heart disease and osteoporosis

Study design Persons enrolled on Tennesse Medicaid programme –30-74 years –Excluded if at high risk of death e.g. LTOT/resp failure All courses of azithromycin (347,795) Matched control periods –No antibiotics (1,391,180) –Amoxicillin – not proarrhythmic (264,626) Primary end points –Cardiovascular death/ all cause mortality Analysis adjusted to account for indication for antibiotic and propensity score (risk of death)

Azithromycin v no antibiotics

Azithromycin v amoxicillin

Risk of death according to underlying cardiovascular risk

He needs glasses, walks with a frame and uses a hearing aid

CT scan shows bronchiectasis and emphysema, sputum cultures not done

Cystic fibrosis Renna et al J Clin Invest. 2011; 121(9):3554–3563 Long term azithromycin

Possible mechanisms Autophagia –Intracellular material ingested into phagosomes and destroyed by fusion with acid-rich lysosomes –Macrophages Azithromycin –Raised lysosomal pH –Inhibited destructive enzymes –Impaired phagocyte-lysosome fusion –Inhibited cytokine release by immune cells Renna et al J Clin Invest. 2011; 121(9):3554–3563

Things to think about... Selecting patients that will benefit –Other options tried first? Smoking cessation Vaccines/rehab Selecting patients less likely to experience harm –Cardiovascular screening/ECG? –Audiometry? –Sputum for NTM – how many? Dose, duration, monitoring, follow up? Protocol and audit...

Azithromycin pharmacokinetics