Pediatric Pulmonology 50:105 (2015)

Response to Letter

We like to thank Willekens et al. for their comments related to our study assessing the efficacy of oral azithromycin in CF patients not infected with Pseudomonas aeruginosa.1 The study was designed as a 6 months placebo controlled randomized controlled trial with a 6 months open label extension; the latter being the focus of our recent publication.2 We agree that this study cannot provide sufficient evidence for the long-term efficacy of azithromycin beyond a 1 year period. Long-term treatment data are important to define the adequate balance between efficacy and potential side effects that could include the development of antibiotic resistant bacteria as well as inadequately treated undiagnosed mycobacterial disease for which macrolides are often required as part of an effective multidrug antibiotic regimen. As outlined by the authors previous data sets have suggested that azithromycin may lose efficacy over time. An analysis of systemic inflammatory markers performed in our study did demonstrate a more pronounced effect after 28 days versus 164 days of treatment that would support this concept.3 However, it is problematic to solely rely on observational data to determine the potential loss of efficacy over time. The frequency of pulmonary exacerbations is known to increase as the disease progresses and it is difficult to dissect the natural history from the lack of efficacy of an intervention in this setting. In addition, the population of P. aeruginosa infected patients with a large range in age and disease severity described by Willekens et al. differs from the group of P. aeruginosa negative pediatric patients with mild disease included in our study and findings should not be simply extrapolated to populations with different clinical characteristics. While it is unlikely that long-term placebo controlled trials will be performed to provide us with strong evidence to address this question, analyses of large cohorts followed in national or international data bases in parallel to matched controls may further clarify the risk/benefit ratio of longterm exposure of CF patients to azithromycin beyond 12 months. In the meantime, we should be cautious not to base our judgment prematurely on the current evidence, as there is also a risk of withdrawing potentially beneficial therapy from patients who could benefit from ongoing treatment. ß 2014 Wiley Periodicals, Inc.

——FELIX RATJEN MD, PhD Division of Respiratory Medicine Department of Pediatrics Hospital for Sick Children University of Toronto, Toronto, ON —MICHAEL ANSTEAD MD University of Kentucky Lexington, Kentucky —LARRY LANDS MD, PhD Division of Respiratory Medicine, Montreal Children’s Hospital, Montreal, QC —NICOLE MAYER-HAMBLETT PhD Department of Pediatrics Seattle Children’s Hospital Seattle, Washington University of Washington Seattle, Washington —LISA SAIMAN MD, MhD Pediatric Infectious Diseases Columbia Medical Center New York, New York REFERENCES 1. Willekens et al. 2. Saiman L, Mayer-Hamblett N, Anstead M, Lands LC, Kloster M, Goss CH, Rose LM, Burns JL, Marshall BC, Ratjen F, the AZ0004 Macrolide Study Team. Open-label, follow-on study of azithromycin in pediatric patients with CF uninfected with Pseudomonas aeruginosa. Ped Pulmonol 2012;47:641–648. 3. Ratjen F, Saiman L, Mayer-Hamblett N, Lands LC, Kloster M, Thompson V, Emmett P, Marshall B, Accurso F, Sagel S, Anstead M. Effect of azithromycin on systemic markers of inflammation in cystic fibrosis patients uninfected with Pseudomonas aeruginosa. Chest 2012;142:1259–1266.



Correspondence to: Felix Ratjen, Division of Respiratory Medicine, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, ON. E-mail: [email protected] Accepted 7 March 2014. DOI 10.1002/ppul.23048 Published online 4 April 2014 in Wiley Online Library (wileyonlinelibrary.com).

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