Review articleMacrolides and ketolides: azithromycin, clarithromycin, telithromycin
Section snippets
Chemistry
Erythromycin is a macrolide antibiotic whose structure consists of a macrocyclic 14-membered lactone ring attached to two sugar moieties (a neutral sugar, cladinose, and an amino sugar, desosamine). In the acidic environment of the stomach, it is rapidly degraded to the 8,9-anhydro-6,9-hemiketal and then to the 6,9,9,12-spiroketal form. The hemiketal intermediate may be responsible for the gastrointestinal adverse effects associated with erythromycin [1].
Clarithromycin (6-O-methylerythromycin)
Mechanism of action and resistance
The macrolide and ketolide antimicrobials exert their antibacterial effects by reversibly binding to the 50s subunit of the bacterial ribosome. This interaction inhibits RNA-dependent protein synthesis by preventing transpeptidation and translocation reactions [2]. Both the macrolides and ketolides bind to domain V of the 23S ribosomal RNA (rRNA) [7]. The ketolides bind with a 10- to 100-fold higher affinity to the ribosome than erythromycin. Additionally, the ketolides, unlike the macrolides,
Pharmacokinetics
The structural alterations to the erythromycin base used to synthesize the advanced macrolides and ketolides result in improved pharmacokinetic properties. Because erythromycin is degraded in an acidic environment, oral bioavailability is variable and depends on the preparation studied. Clarithromycin and azithromycin are more acid-stable and have greater oral bioavailability (55% and 37%, respectively) [14], [15]. When taken with meals the peak plasma concentration of clarithromycin
Spectrum of activity
Guidelines from the National Committee for Clinical Laboratory Standards provide the following interpretation of in vitro MICs for clarithromycin and azithromycin [38]. For S pneumoniae, susceptibility breakpoints are less than or equal to 0.25 mg/L and less than or equal to 0.5 mg/L for clarithromycin and azithromycin, respectively. The corresponding resistance breakpoints are greater than or equal to 1 mg/L and greater than or equal to 2 mg/L. The breakpoint for susceptibility against
Upper respiratory tract infections
Clarithromycin, azithromycin, and telithromycin are effective against the most frequently isolated bacterial causes of pharyngitis, otitis media, and sinusitis. A 5-day course of either the extended-release formulation of clarithromycin, azithromycin, or telithromycin is equally as effective as a 10-day course of penicillin for the treatment of streptococcal pharyngitis [3], [54], [55], [56]. In comparative trials, clarithromycin has proved to be equivalent to amoxicillin,
Adverse effects
Azithromycin, clarithromycin, and telithromycin are well tolerated. Gastrointestinal intolerance is the primary adverse side effect of these agents, but occurs at a significantly reduced rate when compared with erythromycin [41]. The most common adverse effects reported with azithromycin were diarrhea (3.6%); nausea (2.6%); abdominal pain (2.5%); and headache or dizziness (1.3%). Laboratory abnormalities were infrequent and minor including transient increases in transaminases in 1.5% of
Drug interactions
Several reviews have discussed drug interactions between either clarithromycin or azithromycin and other agents [34], [162]. Clarithromycin, like erythromycin, is oxidized by the cytochrome P-450 system, primarily the CYP3A4 subclass of hepatic enzymes [163]. This converts clarithromycin to a nitrosalkalane metabolite that forms an inactive metabolite-enzyme complex by binding to the iron of the CYP3A4 enzyme [34]. This interaction inhibits the CYP3A4 enzymes resulting in decreased clearance of
Summary
The advanced macrolides (azithromycin and clarithromycin) and ketolides (telithromycin) are structural analogues of erythromycin that have similar mechanisms of action. These antimicrobials have several distinct advantages over erythromycin including the following: improved oral bioavailability, longer half-life allowing once- or twice-daily administration, higher tissue concentrations, enhanced antimicrobial activity, and less gastrointestinal adverse effects. Clarithromycin and azithromycin
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