ORIGINAL ARTICLE AIRWAY DISEASES Lack of efficacy of long-term, low-dose azithromycin in chronic rhinosinusitis: a randomized controlled trial W. J. Videler 1 , L. Badia 2 , R. J. Harvey 2,3 , S. Gane 2 , C. Georgalas 1 , F. W. van der Meulen 1 , D. J. Menger 1 , M. T. Lehtonen 4 , S. K. Toppila-Salmi 4 , S. I. Vento 5 , M. Hyto ¨ nen 5 , P. W. Hellings 6 , L. Kalogjera 7 , V. J. Lund 2 , G. Scadding 2 , J. Mullol 8 & W. J. Fokkens 1 1 Department of Otorhinolaryngology, Academic Medical Centre, Amsterdam, the Netherlands; 2 Royal National Throat, Nose & Ear Hospital, London, UK; 3 Rhinology and Skull Base, Department of Otolaryngology/Skull Base Surgery, St Vincents Hospital, University of New South Wales, Sydney, Australia; 4 Department of Otorhinolaryngology, Tampere University Hospital, Tampere; 5 Department of Otorhinolaryngology, Head & Neck Surgery, Helsinki University Central Hospital, Helsinki, Finland; 6 Department of Otorhinolaryngology, University Hospital, Faculty of Medicine, University of Leuven, Leuven, Belgium; 7 Department of Otorhinolaryngology, Head & Neck Surgery, University Hospital ‘‘Sisters of Charity’’, University of Zagreb, Zagreb, Croatia; 8 Rhinology Unit & Smell Clinic, Department of Otorhinolaryngology, Hospital Clinic, IDIBAPS, CIBERES, Barcelona, Catalonia, Spain To cite this article: Videler WJ, Badia L, Harvey RJ, Gane S, Georgalas C, van der Meulen FW, Menger DJ, Lehtonen MT, Toppila-Salmi SK, Vento SI, Hyto ¨ nen M, Hellings PW, Kalogjera L, Lund VJ, Scadding G, Mullol J, Fokkens WJ. Lack of Efficacy of long-term, low-dose azithromycin in chronic rhinosinusitis: a random- ized controlled trial. Allergy 2011; 66: 1457–1468. Chronic rhinosinusitis (CRS) is defined in the European Posi- tion Paper on rhinosinusitis and nasal polyps (EP 3 OS) as the presence of two or more symptoms of which one should be either nasal blockage/congestion or nasal discharge combined with facial pain/pressure and/or reduction/loss of smell for more than 12 weeks (1). This definition is completed with accompanying nasal endoscopic signs and/or corresponding mucosal changes on CT scan. In the last decades, the man- agement of CRS has improved substantially. According to the EP 3 OS-management-schemes, patients with CRS are pri- marily treated with nasal saline irrigation, intranasal cortico- steroids and in more severe cases with antibiotics and/or systemic corticosteroids, especially when nasal polyps are prominent. In patients who do not optimally respond to this Keywords antibiotic treatment; azithromycin; chronic rhinosinusitis; long-term low dose; nose diseases; nasal polyps; oral administration; paranasal sinus diseases; randomized controlled trial; sinusitis. Correspondence W. J. Fokkens, MD, PhD, Department of Otorhinolaryngology, Academic Medical Centre (AMC), Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. Tel.: +31 20 5663789 Fax: +31 20 6913850 E-mail: W.J.Fokkens@amc.uva.nl Accepted for publication 26 July 2011 DOI:10.1111/j.1398-9995.2011.02693.x Edited by: Anthony Frew Abstract Background: In persistent chronic rhinosinusitis (CRS), conventional treatment is often insufficient. Long-term, low-dose administration of macrolides has been suggested as a treatment option. The MACS (Macrolides in chronic rhinosinusitis) study is a randomized placebo-controlled trial evaluating the efficacy of azithromy- cin (AZM) in CRS. Methods: We describe a group of patients with recalcitrant CRS with and without nasal polyps unresponsive to optimal medical and (in 92% also) surgical treatment. Patients were treated with AZM or placebo. AZM was given for 3 days at 500 mg dur- ing the first week, followed by 500 mg per week for the next 11 weeks. Patients were monitored until 3 months post-therapy. The assessments included Sino-Nasal Out- come Test-22 (SNOT-22), a Patient Response Rating Scale, Visual Analogue Scale (VAS), Short Form-36 (SF-36), rigid nasal endoscopy, peak nasal inspiratory flow (PNIF), Sniffin’ Sticks smell tests and endoscopically guided middle meatus cultures. Results: Sixty patients with a median age of 49 years were included. Fifty per cent had asthma and 58% had undergone revision sinus surgery. In the SNOT-22, Patient Response Rating Scale, VAS scores and SF-36, no significant difference between the AZM and the placebo groups was demonstrated. Nasal endoscopic findings, PNIF results, smell tests and microbiology showed no relevant significant differences between the groups either. Conclusion: At the investigated dose of AZM over 3 months, no significant benefit was found over placebo. Possible reasons could be disease severity in the investi- gated group, under-dosage of AZM and under-powering of the study. Therefore, more research is urgently required. Allergy Allergy 66 (2011) 1457–1468 ª 2011 John Wiley & Sons A/S 1457