Macrolide

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The macrolides are a group of drugs (typically antibiotics) whose activity stems from the presence of a macrolide ring, a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14, 15 or 16-membered. Macrolides belong to the polyketide class of natural products.

Erythromycin. The macrolide ring is the lactone (cyclic ester) at upper left.

Clarithromycin

Roxithromycin

Members

Common antibiotic macrolides

• Azithromycin (Zithromax, Zitromax, Sumamed, Azitrox) - Unique, does not inhibit CYP3A4
• Clarithromycin (Biaxin, Fromilid, Klacid, Klabax, Lekoklar)
• Dirithromycin (Dynabac)
• Erythromycin
• Roxithromycin (Rulid, Surlid,Roxid)
• Telithromycin

Developmental macrolides

• Carbomycin A
• Josamycin
• Kitasamycin
• Midecamicine/midecamicine acetate
• Oleandomycin
• Spiramycin
• Troleandomycin
• Tylosin/tylocine (Tylan)

Ketolides

Ketolides are 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.

• Telithromycin (Ketek)
• Cethromycin

Others include spiramycin (used for treating toxoplasmosis), ansamycin, oleandomycin, carbomycin and tylocine.

Non-antibiotic macrolides

The drugs tacrolimus (Prograf) and sirolimus which are used as immunosuppressants, are also macrolide. They have similar activity to ciclosporin.

Toxic macrolides

A variety of toxic macrolides produced by bacteria have been isolated and characterized, such as the mycolactones.

Uses

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, staphylococci and enterococci are usually susceptible to macrolides. Unlike penicillin, macrolides have been shown to be effective against mycoplasma, mycobacteria, some rickettsia, and chlamydia.

Mechanism of action

Macrolides are protein synthesis inhibitors. The mechanism of action of macrolides is inhibition of bacterial protein biosynthesis, and they are thought to do this by preventing peptidyltransferase from adding the peptidyl attached to tRNA to the next amino acid^[1] (similarily to chloramphenicol)^{[citation needed]} as well as inhibiting ribosomal translocation.^[1] Another potential mechanism is premature dissociation of the peptidyl-tRNA from the ribosome.^[2]

Macrolide antibiotics do so by binding reversibly to the subunit 50S of the bacterial ribosome. 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).^[3][4] The successful results of macrolides in DPB stems from controlling symptoms through immunomodulation (adjusting the immune response),^[4] with the added benefit of low-dose requirements.^[3]

With macrolide therapy in DPB, great reduction in bronchiolar inflammation and damage is achieved through suppression of not only neutrophil granulocyte proliferation, but also lymphocyte activity and obstructive secretions in airways.^[3] The antimicrobial and antibiotic effects of macrolides, however, are not believed to be involved in their beneficial effects toward treating DPB.^[5] 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.^[3]

Resistance

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.

Azithromycin has been used to treat strep throat (Group A streptococcal (GAS) infection caused by Streptococcus pyogenes) in penicillin-sensitive patients, however macrolide resistant strains of GAS are not uncommon. Cephalosporin is another option for these patients.

Side effects

A 2008 British Medical Journal article highlights that the combination of macrolides and statins (used for lowering cholesterol) is not advisable and can lead to debilitating myopathy^[6]. This is because macrolides are potent inhibitors of the cytochrome P450 system, particularly of CYP3A4. Macrolides, mainly erythromycin and clarithromycin, also have a class effect of QT prolongation which 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 duodenum in bile from the liver. This can lead to a build up of the product in the system, and so causing nausea.

See also

• Lyme disease

Bibliography

• Ōmura, Satoshi (2002). Macrolide antibiotics: chemistry, biology, and practice (2nd ed.). Boston: Academic Press. ISBN 0-12-526451-8. 

References

External links

• Structure Activity Relationships "Antibacterial Agents; Structure Activity Relationships," André Bryskier MD; beginning at pp143