Macrolides
المؤلف:
Stefan Riedel, Jeffery A. Hobden, Steve Miller, Stephen A. Morse, Timothy A. Mietzner, Barbara Detrick, Thomas G. Mitchell, Judy A. Sakanari, Peter Hotez, Rojelio Mejia
المصدر:
Jawetz, Melnick, & Adelberg’s Medical Microbiology
الجزء والصفحة:
28e , p403-404
2025-10-12
219
Erythromycin is obtained from Streptomyces erythreus and has the chemical formula C37H67NO13. Drugs related to erythromycin are clarithromycin, azithromycin, and others. Macrolides attach to a receptor (a 23S rRNA) on the 50S subunit of the bacterial ribosome. They inhibit protein synthesis by interfering with translocation reactions and the formation of initiation complexes. Resistance to macrolides results from an alteration (methylation) of the rRNA receptor. This is under the control of a transmissible plasmid. Other mechanisms include inactivating enzymes and active efflux of drug encoded by mef and msr genes. The activity of erythromycins is greatly enhanced at alkaline pH.
Macrolides in concentrations of 0.1–2 μg/mL are active against Gram-positive bacteria, including pneumococci, streptococci, and corynebacteria. M. pneumoniae, Chlamydia trachomatis, L. pneumophila, and Campylobacter jejuni are also susceptible. Resistant variants occur in susceptible microbial populations and tend to emerge during treatment, especially in staphylococcal infections.
Erythromycins may be drugs of choice in infections caused by the organisms listed and are substitutes for penicillins in persons hypersensitive to the latter. Erythromycin stearate, succinate, or estolate orally four times a day yields serum levels of 0.5–2 μg/mL. Other forms are given intravenously.
Undesirable side effects are drug fever, mild gastrointestinal upsets, and cholestatic hepatitis as a hypersensitivity reaction, especially to the estolate. Hepatotoxicity may be increased during pregnancy. Cardiac arrhythmias specifically ventricular tachycardia with QT prolongation has been described with both oral and intravenous erythromycin. Coadministration of CYP3A-inhibitors markedly increases the risk of this occurring. Erythromycin tends to increase the levels of simultaneously administered anticoagulants, cyclosporine, and a variety of other drugs by depressing microsomal enzymes.
Clarithromycin and azithromycin are azalides that are chemically related to erythromycin. Similar to erythromycin, both clarithromycin and azithromycin are active against staphylococci and streptococci. Clarithromycin has enhanced activity against L. pneumophila, Helicobacter pylori, Moraxella catarrhalis, C. trachomatis, and Borrelia burgdorferi. Azithromycin has enhanced activity against C. jejuni, H. influenzae, M. pneumoniae, M. catarrhalis, N. gonorrhoeae, and B. burgdorferi. Both drugs are active against Mycobacterium avium complex, and both drugs inhibit most strains of Mycobacterium chelonei and Mycobacterium fortuitum. Bacteria resistant to erythromycin are also resistant to clarithromycin and azithromycin. The chemical modifications prevent the metabolism of clarithromycin and azithromycin to inactive forms, and the drugs are given twice daily (clarithromycin) or once daily (azithromycin). Both drugs are associated with a much lower incidence of gastrointestinal side effects than erythromycin.
The ketolides are semisynthetic derivatives of erythromycin. They are more active than the macrolides, particularly against some macrolide-resistant bacteria, and have improved pharmacokinetics. Telithromycin is the agent currently approved for use in the United States. It is administered orally for the treatment of acute upper and lower respiratory tract infections. Its mechanism of action and side-effect profile are similar to those of the macrolides. Rare reports of severe hepatotoxicity have limited it use in the United States.
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