Azithromycin: Mechanisms of action and their relevance for clinical applications

Article ID	Journal	Published Year	Pages	File Type
5844150	Pharmacology & Therapeutics	2014	21 Pages	PDF

Abstract

Initial, stimulatory effects of azithromycin on immune and epithelial cells, involving interactions with phospholipids and Erk1/2, are followed by later modulation of transcription factors AP-1, NFÎºB, inflammatory cytokine and mucin release. Delayed inhibitory effects on cell function and high lysosomal accumulation accompany disruption of protein and intracellular lipid transport, regulation of surface receptor expression, of macrophage phenotype and autophagy. These later changes underlie many immunomodulatory effects of azithromycin, contributing to resolution of acute infections and reduction of exacerbations in chronic airway diseases. A sub-group of post-transplant bronchiolitis patients appears to be sensitive to azithromycin, as may be patients with severe sepsis. Other promising indications include chronic prostatitis and periodontitis, but weak activity in malaria is unlikely to prove crucial. Long-term administration of azithromycin must be balanced against the potential for increased bacterial resistance. Azithromycin has a very good record of safety, but recent reports indicate rare cases of cardiac torsades des pointes in patients at risk.

Keywords

Cmax PI3K MMP TNFα LPS COX Jnk SMC BOS MIC FGF ERK DPB BAL STD AP-1 CFTR cPLA2 TLR i.p LC3 CBP GM-CSF tmax DTH SAA RCT ARDS VAP LRTI MUC5AC MDR1 SREBP DNFB c-Jun NH(2)-terminal kinase AECOPD MODS granulocyte–macrophage colony stimulating factor time to Cmax GvH p.o cytoplasmic phospholipase A2 Mucin 5AC Acute exacerbations of COPD NGU PMNL i.v graft versus host reaction AUC MPO MAPK NFκB ROS t1/2 Azithromycin STAT Macrolide antibiotic i.t non-gonococcal urethritis Los interleukin Intranasal COPD Chronic obstructive pulmonary disease sexually transmitted disease Immunomodulation Mechanical ventilation tumor necrosis factor alpha Toll-like receptor Community acquired pneumonia Volume of distribution Minimum inhibitory concentration Delayed type hypersensitivity intraperitoneal Intravenous cationic amphiphilic drugs intratracheal Oral dinitrofluorobenzene Smooth muscle cell T helper cell Natural killer cells Bronchiolitis obliterans syndrome Multiple organ dysfunction syndrome Acute respiratory distress syndrome cyclo-oxygenase broncho-alveolar lavage CAD length of stay Lower respiratory tract infection Peak plasma concentration Pharmacokinetics pharmacokinetic Vascular endothelial growth factor Vascular Endothelial Growth Factor (VEGF)fibroblast growth factor nuclear factor kappaB phosphatidylinositol Phosphatidylserine phosphoinositide-3-kinase Cystic fibrosis polymorphonuclear leukocytes Bacterial lipopolysaccharide signal transducers and activators of transcription Metalloproteinase Mechanisms of action myeloperoxidase hazard ratio odds ratio Plasma half-life diffuse panbronchiolitis Serum amyloid A protein sterol regulatory element binding protein activator protein-1 multidrug resistance protein 1 mitogen-activated protein kinase Chronic bacterial prostatitis prostaglandin randomized controlled clinical trial Clinical efficacy CaP extracellular signal-regulated kinase not reported Reactive oxygen species