1. Azithromycin – for better or worse in chronic lung infection? Professor Emma Baker Professor of Clinical Pharmacology St George's, University of London ebaker@sgul.ac.uk

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

3. 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?

4. 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

7. 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

8. Azithromycin 250mg daily

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

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

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

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

13. Comorbidities include diabetes mellitus, ischaemic heart disease and osteoporosis

14. Study design Persons enrolled on Tennesse Medicaid programme 1992-2006 –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)

15. Azithromycin v no antibiotics

16. Azithromycin v amoxicillin

17. Risk of death according to underlying cardiovascular risk

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

22. CT scan shows bronchiectasis and emphysema, sputum cultures not done

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

24. 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

25. 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...

26. Azithromycin pharmacokinetics