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The anti-inflammatory potential of macrolides was first appreciated with the successful use of erythromycin in the treatment of diffuse panbronchiolitis, a disease principally affecting the Japanese, and characterised by a persistent neutrophilic inflammatory infiltrate of the bronchi. While there are only limited data on the efficacy of other macrolides in treating this condition,1 the observation has generated considerable interest in examining the role of macrolides in other respiratory diseases where chronic airways inflammation is a prominent feature.
Azithromycin (AZM) is a 15-membered macrolactam ring macrolide which, in randomised controlled studies, has demonstrated a beneficial role in the treatment of cystic fibrosis (CF)2–5 despite its lack of direct bactericidal or bacteriostatic activity against Pseudomonas aeruginosa. More recent (albeit smaller) studies have suggested a role for AZM in the treatment of bronchiolitis obliterans syndrome (BOS)6 and asthma,7 with a common finding in both being its ability to reduce airway neutrophilia. Such observations have focused attention on understanding how AZM and other macrolides may modulate host-pathogen interactions in chronic lung infection and their role as an immunomodulatory agent in both respiratory and non-respiratory settings. Clinical studies have usually been designed to study an individual macrolide agent, but it is likely that the findings in such trials represent a “class effect”. Although some in vitro experiments have suggested subtle differences between individual class members, the in vivo significance of these observations is uncertain.
MODULATION OF HOST-PATHOGEN INTERACTIONS
The direct antimicrobial activity of macrolides against Gram-positive bacteria results from inhibition of bacterial protein synthesis. Although AZM has little direct activity against Gram-negative organisms, it has been shown to modulate bacterial virulence factors and thus affect the outcome of chronic infections with organisms such as P aeruginosa. Quorum sensing is a sophisticated mechanism whereby pathogen-derived molecules act as auto-inducers and trigger a …
Funding: The work in the authors’ laboratory is funded by the MRC, the Wellcome Trust, Asthma UK, the British Lung Foundation, Papworth Hospital, Cambridge NIHR-Biomedical Research Centre and non-commercial grants from GSK and Astra-Zeneca.
Competing interests: None.