巨環類 Macrolides

 Macrolides Antibiotic Agents

Uses

Antibiotic macrolides are used to treat infections caused by Gram-positive bacteria, Streptococcus pneumoniae, and Haemophilus influenzae 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 Legionella pneumophila, mycoplasma, mycobacteria, some rickettsia, and chlamydia.

Macrolides are not to be used on non-ruminant herbivores, such as horses and rabbits. They rapidly produce a reaction causing fatal digestive disturbance. ^[1] It can be used in horses less than one year old, but care must be taken that other horses (such as a foal's mother) do not come in contact with the macrolide treatment.

[edit] Mechanism of action

[edit] Antibacterial

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^[2] (similarly to chloramphenicol)^{[citation needed]} as well as inhibiting ribosomal translocation.^[2] Another potential mechanism is premature dissociation of the peptidyl-tRNA from the ribosome.^[3]

Macrolide antibiotics do so by binding reversibly to the P site on 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, transported into the site of infection.^{[citation needed]}

[edit] Immunomodulation

[edit] Diffuse panbronchiolitis

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).^{[4] [5]} The successful results of macrolides in DPB stems from controlling symptoms through immunomodulation (adjusting the immune response),^[5] with the added benefit of low-dose requirements.^[4]

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.^[4] The antimicrobial and antibiotic effects of macrolides, however, are not believed to be involved in their beneficial effects toward treating DPB.^[6] 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.^[4]

[edit] 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.

[edit] 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.^[7] 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, thereby causing nausea. In infants the use of erythromycin has been associated with pyloric stenosis.^[8][9]

[edit] Bibliography

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

[edit] References

[edit] External links

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

Uses

Antibiotic macrolides are used to treat infections caused by Gram-positive bacteria, Streptococcus pneumoniae, and Haemophilus influenzae 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 Legionella pneumophila, mycoplasma, mycobacteria, some rickettsia, and chlamydia.

Macrolides are not to be used on non-ruminant herbivores, such as horses and rabbits. They rapidly produce a reaction causing fatal digestive disturbance. ^[1] It can be used in horses less than one year old, but care must be taken that other horses (such as a foal's mother) do not come in contact with the macrolide treatment.

[edit] Mechanism of action

[edit] Antibacterial

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^[2] (similarly to chloramphenicol)^{[citation needed]} as well as inhibiting ribosomal translocation.^[2] Another potential mechanism is premature dissociation of the peptidyl-tRNA from the ribosome.^[3]

Macrolide antibiotics do so by binding reversibly to the P site on 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, transported into the site of infection.^{[citation needed]}

[edit] Immunomodulation

[edit] Diffuse panbronchiolitis

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).^{[4] [5]} The successful results of macrolides in DPB stems from controlling symptoms through immunomodulation (adjusting the immune response),^[5] with the added benefit of low-dose requirements.^[4]

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.^[4] The antimicrobial and antibiotic effects of macrolides, however, are not believed to be involved in their beneficial effects toward treating DPB.^[6] 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.^[4]

[edit] 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.

[edit] 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.^[7] 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, thereby causing nausea. In infants the use of erythromycin has been associated with pyloric stenosis.^[8][9]

[edit] Bibliography

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

[edit] References

[edit] External links

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