Azithromycin: Mechanisms of action and their relevance for clinical applications
Introduction
Azithromycin, a second generation macrolide, broad-spectrum antibacterial, has received increasing attention in recent years because of additional effects on host-defence reactions and chronic human diseases. It is the prototype 15-membered lactone ring azalide, synthesized in the early 1980s as a semi-synthetic derivative of erythromycin. Discovered around the same time by researchers at Pfizer in the United States (Bright & Hauske, 1984) and at PLIVA, Croatia (Kobrehel et al., 1982), PLIVA patented first and licensed the compound to Pfizer. With much improved pharmacokinetic properties over erythromycin, azithromycin became the most widely used broad-spectrum antibacterial in North America. Pfizer Inc's Arthur E. Girard and Gene Michael Bright, together with PLIVA's Slobodan Djokic (posthumously) and Gabrijela Kobrehel, received in 2000 the American Chemical Society's award of “Heroes of Chemistry who have promoted human welfare in the area of health” for their discovery of Zithromax® (azithromycin).
Azithromycin shares the same mechanism of antibacterial action as other macrolide antibiotics (Allen, 2002), but accumulates more effectively in phagocytes, thus being delivered in high concentrations to sites of infection (Miossec-Bartoli et al., 1999, Wilms et al., 2006). It also inhibits bacterial quorum-sensing and reduces formation of biofilm and mucus production, which extend its range of antibacterial actions (Tateda et al., 2001, Hoffmann et al., 2007). As an antibiotic, azithromycin is indicated for respiratory, urogenital, dermal and other bacterial infections, but has beneficial effects in chronic inflammatory disorders such as diffuse panbronchiolits, bronchiolitis obliterans and rosacea. Efficacy in these conditions is ascribed to immunomodulatory effects on innate and adaptive immune responses. Modulation of host response reactions also accounts, at least partially, for beneficial effects in cystic fibrosis, non-cystic fibrosis bronchiectasis, bronchial obliterans syndrome (BOS) and chronic obstructive pulmonary disease (COPD).
Azithromycin is well-tolerated and has a very good record of safety. Although macrolides have a class warning for potential cardiac QT prolongation, azithromycin does not show this effect under experimental conditions (Milberg et al., 2002). Until recently, only a handful of cases of QT prolongation had been reported for patients treated with the drug (Kezerashvili et al., 2007). This is mainly because azithromycin, unlike other macrolide antibiotics, does not interact with CYP3A4, despite a minor interaction with the anti-coagulant warfarin (Kanoh and Rubin, 2010, Mergenhagen et al., 2013). Recently, evidence for increased risk of QT prolongation with azithromycin has appeared, but mainly in patients with greater susceptibility to adverse cardiac effects (Giudicessi & Ackerman, 2013).
We review here the antibacterial actions and pharmacokinetics of azithromycin, as well as its immunomodulatory effects and the mechanisms involved, in comparison to other macrolide antibiotics. We discuss the main clinical uses of azithromycin, drawing attention to emerging indications and emphasising how its pharmacokinetic properties and immunomodulatory actions contribute to the effects observed.
Section snippets
Inhibitory actions
Azithromycin, like other macrolide antibiotics, inhibits bacterial protein synthesis by binding to and interfering with the assembly of the 50S large ribosomal subunit and the growth of the nascent polypeptide chain (Champney and Burdine, 1998, Champney et al., 1998, Hansen et al., 2002). It binds at the polypeptide exit tunnel, close to the peptidyl transferase center (PTC) on the 23S rRNA, but does not inhibit PT activity, in contrast to larger macrocyclic antibiotics. The basicity of
Pharmacokinetics
Early pharmacokinetic (PK) studies on azithromycin, indicating low plasma levels, were incorrectly interpreted as reflecting poor PK properties. Azithromycin is now known to have a large volume of distribution, achieving high tissue concentrations and is efficiently delivered to sites of infection. Compared with older generation macrolides, it is more stable in acidic media and has a longer half-life, allowing for once a day or even single dose treatment (Amsden, 1995, Amsden, 2001). Moreover,
Immunomodulatory activities
Early studies on macrolide antibiotics and host defense revealed inhibitory effects on neutrophils in vitro, on experimental inflammation (Culic et al., 2001) and particularly actions on cytokine release (Bartold et al., 2013). While azithromycin was shown in the late 1980s to inhibit inflammation and lysosomal enzyme release in arthritic rats (Carevic & Djokic, 1988), subsequent studies were carried out predominantly with erythromycin, clarithromycin and roxithromycin. All macrolide
Clinical applications in respiratory infections and airway inflammation
The unique imunomodulatory properties of azithromycin, its broad antibacterial spectrum and exceptional pharmacokinetics, resulting in extensive and sustained tissue penetration, largely account for its disease-modifying effects in infectious or non-infectious inflammatory airways diseases. These coincident properties also explain its indication for upper and lower respiratory tract infections (e.g. acute bacterial sinusitis, community-acquired pneumonia), in which macrolides exert therapeutic
Infections of the urogenital tract and sexually-transmitted infections
Over 90% of an oral dose of azithromycin is excreted via the hepato-biliary system (Ballow et al., 1998, Foulds et al., 1990, Singlas, 1995). Since very little drug is found unchanged in the urine, azithromycin is not suitable for diseases involving significant bacteruria. Due to its optimal systemic distribution and tissue penetration, though, azithromycin accumulates up to 100-fold in a variety of tissues of urological interest (Foulds et al., 1990, Foulds et al., 1991).
Clinical application in sepsis
Sepsis is an overwhelming inflammatory host response to a bacterial stimulus. Several animal studies have shown a significant anti-inflammatory effect of azithromycin (Table 3) or clarithromycin in experimental sepsis. Pretreatment of mice with azithromycin improved survival and attenuated plasma levels of TNFα in LPS-induced shock (Ivetic Tkalcevic et al., 2006, Tong et al., 2011) and additional immunomodulatory effects have been described for clarithromycin. Administered i.v. immediately
Skin disease
Macrolide antibiotics, are widely used for the topical treatment of acne and rosacea and their use for these and other skin disorders has been reviewed (Alzolibani & Zedan, 2012). In several small studies, oral azithromycin (for 2–4 weeks) provided significant improvement in intractable rosacea. In one healthy volunteer-controlled study, standard dosing with azithromycin for 4 weeks to 17 patients with rosacea, reduced inflammatory score and ameliorated the raised oxidave burst
Safety
A concern about the use of macrolide antibiotics for long-term treatment of chronic inflammatory diseases, is the possibility of increased bacterial resistance, though the relationship between long-term use and increased resistance is still uncertain (Cameron et al., 2012). A recent meta-analysis of six RCTs on the effects of long-term azithromycin in chronic lung diseases, revealed that while bacterial colonization decreased by 45%, there was a 2.7-fold increase in bacterial resistance (Li et
Conclusions
As a broad-spectrum antibacterial, azithromycin shares the same mechanism of action as other macrolide antibiotics and its range of activity is extended through inhibition of bacterial quorum-sensing and biofilm. Accumulating more effectively than other macrolides in cells, particularly circulating phagocytes, it is delivered in high concentrations to sites of infection. This important feature, combined with the extended plasma half-life of azithromycin, often allows effective single-dose
Conflict of interest
GPP and RV declare that they have no conflicts of interest.
Acknowledgments
MJP has collaborated with Novo Nordisk and serves as an advisor to Leo Pharma A/S and Xellia Pharmaceuticals ApS. VEH is an employee of Fildelta d.o.o. and both MJP and VEH are previous employees of PLIVA and GlaxoSmithKline. EGB has received unrestricted educational grants from Abbott Hellas SA (program 70/3/7447 of the University of Athens). He also serves as an advisor to AbbVie SA.
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