Review article
Macrolides and ketolides: azithromycin, clarithromycin, telithromycin

https://doi.org/10.1016/j.idc.2004.04.010Get rights and content

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

First page preview

First page preview
Click to open first page preview

References (170)

  • L.R. Weiss

    Open-label, randomized comparison of the efficacy and tolerability of clarithromycin, levofloxacin, and cefuroxime axetil in the treatment of adults with acute bacterial exacerbations of chronic bronchitis

    Clin Ther

    (2002)
  • J.L. Adler et al.

    Phase III, randomized, double-blind study of clarithromycin extended-release and immediate-release formulations in the treatment of patients with acute exacerbation of chronic bronchitis

    Clin Ther

    (2000)
  • D. Allin et al.

    Comparison of once- and twice-daily clarithromycin in the treatment of adults with severe acute lower respiratory tract infections

    Clin Ther

    (2001)
  • A. Anzueto et al.

    Comparison of the efficacy of extended-release clarithromycin tablets and amoxicillin/clavulanate tablets in the treatment of acute exacerbation of chronic bronchitis

    Clin Ther

    (2001)
  • R. Wilson et al.

    A comparison of gemifloxacin and clarithromycin in acute exacerbations of chronic bronchitis and long-term clinical outcomes

    Clin Ther

    (2002)
  • G. Hoeffken et al.

    The efficacy and safety of two oral moxifloxacin regimens compared to oral clarithromycin in the treatment of community-acquired pneumonia

    Respir Med

    (2001)
  • M.H. Gotfried et al.

    A controlled, double-blind, multicenter study comparing clarithromycin extended-release tablets and levofloxacin tablets in the treatment of community-acquired pneumonia

    Clin Ther

    (2002)
  • W.N. Sokol et al.

    A prospective, double-blind, multicenter study comparing clarithromycin extended-release with trovafloxacin in patients with community-acquired pneumonia

    Clin Ther

    (2002)
  • G.W. Amsden et al.

    Efficacy and safety of azithromycin vs levofloxacin in the outpatient treatment of acute bacterial exacerbations of chronic bronchitis

    Chest

    (2003)
  • L. Hagberg et al.

    Telithromycin in the treatment of community-acquired pneumonia: a pooled analysis

    Respir Med

    (2003)
  • C. Carbon et al.

    Telithromycin 800 mg once daily for seven to ten days is an effective and well-tolerated treatment for community-acquired pneumonia

    Clin Microbiol Infect

    (2003)
  • M. Aubier et al.

    Telithromycin is as effective as amoxicillin/clavulanate in acute exacerbations of chronic bronchitis

    Respir Med

    (2002)
  • J.A. Paladino et al.

    Cost-effectiveness of IV-to-oral switch therapy: azithromycin vs cefuroxime with or without erythromycin for the treatment of community-acquired pneumonia

    Chest

    (2002)
  • E. Frank et al.

    A multicenter, open-label, randomized comparison of levofloxacin and azithromycin plus ceftriaxone in hospitalized adults with moderate to severe community-acquired pneumonia

    Clin Ther

    (2002)
  • S. Omura et al.

    Macrolides with gastrointestinal motor stimulating activity

    J Med Chem

    (1987)
  • M.G. Sturgill et al.

    Clarithromycin: review of a new macrolide antibiotic with improved microbiologic spectrum and favorable pharmacokinetic and adverse effect profiles

    Ann Pharmacother

    (1992)
  • S.C. Piscitelli et al.

    Clarithromycin and azithromycin: new macrolide antibiotics

    Clin Pharm

    (1992)
  • C.S. Shain et al.

    Telithromycin: the first of the ketolides

    Ann Pharmacother

    (2002)
  • S. Douthwaite et al.

    Structures of ketolides and macrolides determine their mode of interaction with the ribosomal target site

    J Antimicrob Chemother

    (2001)
  • W.S. Champney et al.

    Superiority of 11,12 carbonate macrolide antibiotics as inhibitors of translation and 50S ribosomal subunit formation in Staphylococcus aureus cells

    Curr Microbiol

    (1999)
  • L.H. Hansen et al.

    The macrolide-ketolide antibiotic binding site is formed by structures in domains II and V of 23S ribosomal RNA

    Mol Microbiol

    (1999)
  • S. Douthwaite et al.

    Macrolide-ketolide inhibition of MLS-resistant ribosomes is improved by alternative drug interaction with domain II of 23S rRNA

    Mol Microbiol

    (2000)
  • A. Tait-Kamradt et al.

    mefE is necessary for the erythromycin-resistant M phenotype in Streptococcus pneumoniae

    Antimicrob Agents Chemother

    (1997)
  • Aventis Pharma. Ketek (telithromycin): briefing document for the FDA Anti-Infective Drug Products Advisory Committee...
  • R. Leclercq et al.

    Bacterial resistance to macrolide, lincosamide, and streptogramin antibiotics by target modification

    Antimicrob Agents Chemother

    (1991)
  • A. Bonnefoy et al.

    Ketolides lack inducibility properties of MLS(B) resistance phenotype

    J Antimicrob Chemother

    (1997)
  • G. Foulds et al.

    The pharmacokinetics of azithromycin in human serum and tissues

    J Antimicrob Chemother

    (1990)
  • H.C. Neu

    The development of macrolides: clarithromycin in perspective

    J Antimicrob Chemother

    (1991)
  • Abbott Laboratories. Biaxin: prescribing information, May, 2003. Available at: http://www.biaxin.com/pdf/biapi.PDF....
  • D.R. Guay et al.

    Pharmacokinetics and tolerability of extended-release clarithromycin

    Clin Ther

    (2001)
  • G. Foulds et al.

    The absence of an effect of food on the bioavailability of azithromycin administered as tablets, sachet or suspension

    J Antimicrob Chemother

    (1996)
  • S. Hopkins

    Clinical toleration and safety of azithromycin

    Am J Med

    (1991)
  • C. Perret et al.

    Pharmacokinetics and absolute oral bioavailability of an 800-mg oral dose of telithromycin in healthy young and elderly volunteers

    Chemotherapy

    (2002)
  • V. Bhargava et al.

    Lack of effect of food on the bioavailability of a new ketolide antibacterial, telithromycin

    Scand J Infect Dis

    (2002)
  • K.W. Garey et al.

    Intravenous azithromycin

    Ann Pharmacother

    (1999)
  • J.L. Ferrero et al.

    Metabolism and disposition of clarithromycin in man

    Drug Metab Dispos

    (1990)
  • L.M. Chiu et al.

    Pharmacokinetics of intravenous azithromycin and ceftriaxone when administered alone and concurrently to healthy volunteers

    J Antimicrob Chemother

    (2002)
  • F. Namour et al.

    Pharmacokinetics of the new ketolide telithromycin (HMR 3647) administered in ascending single and multiple doses

    Antimicrob Agents Chemother

    (2001)
  • F. Fraschini et al.

    The diffusion of clarithromycin and roxithromycin into nasal mucosa, tonsil and lung in humans

    J Antimicrob Chemother

    (1991)
  • K.A. Rodvold et al.

    Intrapulmonary steady-state concentrations of clarithromycin and azithromycin in healthy adult volunteers

    Antimicrob Agents Chemother

    (1997)
  • Cited by (0)

    View full text