The macrolides are a group of drugs (typically
antibiotics) whose activity stems from the presence of a "macrolide ring", a large macrocyclic lactonering to which one or more deoxy sugars, usually cladinoseand desosamine, may be attached. The lactone rings are usually 14, 15 or 16-membered. Macrolides belong to the polyketideclass of natural products.
Common antibiotic macrolides
Azithromycin(Zithromax, Zitromax, Sumamed) - Unique, does not inhibit CYP3A4
Midecamicine/ midecamicine acetate
Ketolidesare a new class of antibiotics that are structurally related to the macrolides. They are used to fight respiratory tract infections caused by macrolide-resistant bacteria.
spiramycin(used for treating toxoplasmosis), ansamycin, oleandomycin, carbomycinand tylocine.
tacrolimus(Prograf), which is used as an immunosuppressant, is also a macrolide. It has similar activity to cyclosporin.
A variety of toxic macrolides produced by bacteria have been isolated and characterized, such as the
Antibiotic macrolides are used to treat infections such as respiratory tract and soft tissue infections. The antimicrobial spectrum of macrolides is slightly wider than that of
penicillin, and therefore macrolides are a common substitute for patients with a penicillin allergy. Beta-hemolytic streptococci, pneumococci, staphylococciand enterococciare usually susceptible to macrolides. Unlike penicillin, macrolides have been shown to be effective against mycoplasma, mycobacteria, some rickettsia, and chlamydia.
Mechanism of action
mechanism of actionof the macrolides is inhibition of bacterial protein biosynthesisby binding reversibly to the subunit 50Sof the bacterial ribosome, thereby inhibiting translocation of peptidyl tRNA. This action is mainly bacteriostatic, but can also be bactericidal in high concentrations. Macrolides tend to accumulate within leukocytes, and are therefore actually transported into the site of infection.
The macrolide antibiotics erythromycin, clarithromycin and roxithromycin have proven to be an effective long-term treatment for the
idiopathic, Asian-prevalent lung disease diffuse panbronchiolitis(DPB).cite journal |author=Keicho N, Kudoh S |title=Diffuse panbronchiolitis: role of macrolides in therapy |journal=Am J Respir Med. |volume=1 |issue=2 |pages=119–131 |year=2002 |pmid=14720066 ] cite journal |author=Lopez-Boado YS, Rubin BK |title=Macrolides as immunomodulatory medications for the therapy of chronic lung diseases |journal=Curr Opin Pharmacol. |volume=8 |issue=3 |pages=286–291 |year=2008 |pmid=18339582 |doi=10.1016/j.coph.2008.01.010 ] The successful results of macrolides in DPB stems from controlling symptoms through immunomodulation(adjusting the immune response), with the added benefit of low-dose requirements.
With macrolide therapy in DPB, great reduction in bronchiolar inflammation and damage is achieved through suppression of not only
neutrophil granulocyteproliferation, but also lymphocyte activity and obstructive secretions in airways. The antimicrobial and antibiotic effects of macrolides, however, are not believed to be involved in their beneficial effects toward treating DPB.cite journal |author=Schultz MJ |title=Macrolide activities beyond their antimicrobial effects: macrolides in diffuse panbronchiolitis and cystic fibrosis |journal=J Antimicrob Chemother. |volume=54 |issue=1 |pages=21–28 |year=2004 |pmid=15190022 |doi=10.1093/jac/dkh309 ] This is evident, as the treatment dosage is much too low to fight infection, and in DPB cases with the occurrence of the macrolide-resistant bacterium " Pseudomonas aeruginosa", macrolide therapy still produces substantial anti-inflammatory results.
The primary means of bacterial resistance to macrolides occurs by post-transcriptional methylation of the 23S bacterial ribosomal RNA. This acquired resistance can be either
plasmid-mediated or chromosomal, i.e through mutation, and results in cross-resistance to macrolides, lincosamides, and streptogramins(an MLS-resistant phenotype).
Two other types of acquired resistance rarely seen include the production of drug-inactivating enzymes (esterases or kinases) as well as the production of active ATP-dependent efflux proteins that transport the drug outside of the cell.
A recent British Medical Journal article highlights that the combination of macrolides and
statins(used for lowering cholesterol) is not advisable and can lead to debilitating myopathyFact|date=August 2008. This is because macrolides are potent inhibitors of the cytochrome P450system, particularly of CYP3A4. Macrolides, mainly erythromycin and clarithromycin, also have a class effect of QT prolongationwhich can lead to torsade de pointes. Macrolides exhibit enterohepatic recycling; that is, the drug is absorbed in the gut and sent to the liver, only to be excreted into the duodenumin bile from the liver. This can lead to a build up of the product in the system causing nausea.
* Macrolide Antibiotics: Chemistry, Biology, and Practice, 2nd Edition, Ed. Satoshi Omura, 2002, Academic Press.
* [http://www.infectio-lille.com/diaporamas/invites/struct-act-duatb05-bryskier.pdf Structure Activity Relationships] "Antibacterial Agents; Structure Activity Relationships," André Bryskier MD; beginning at pp143
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