Chemistry and Pharmacodynamics
Chemical structure
- Macrolides: characterized by a macrocyclic lactone ring
- Ring contains 14‒16 atoms
- 1 or more sugars are attached via glycosidic bonds
- Erythromycin is the prototype drug of the class.
- Ketolides (e.g., telithromycin): similar structure to macrolides
- 14-atom ring
- 1 of the sugars is substituted with a keto group
- Derived from erythromycin
Chemical structure of erythromycin (the prototype drug of the macrolide class), featuring a macrocyclic lactone ring with 2 sugars attached
Image: “Erythromycin” by Edgar181. License: Public Domain
The chemical structure of telithromycin (a ketolide):
Image: “Telithromycin” by Edgar181. License: Public Domain
Notice the similar structure to erythromycin, with a keto group replacing a sugar.
Mechanism of action
- Inhibits bacterial protein synthesis by binding reversibly to the 50S ribosomal subunit
- Binds near the peptidyltransferase center → prevents peptidyl transferase from adding amino acids to a growing peptide (prevents transpeptidation)
- Also inhibits the formation of the 50S subunit
- Limits bacterial growth → bacteriostatic
- Additional effects:
- Antiinflammatory effect by ↓ interleukins and tumor necrosis factor-alpha
- Erythromycin is a motilin receptor agonist at duodenal enterochromaffin cells → has prokinetic properties
The site of action for macrolides on the 50S ribosomal subunit
tRNA: transfer RNA
mRNA: messenger RNA
Pharmacokinetics
| Macrolides | Ketolides | |
|---|---|---|
| Absorption | Erythromycin:
| Rapid absorption |
| Distribution |
|
|
| Metabolism |
|
|
| Excretion |
|
|
Indications
Antimicrobial coverage
- Gram positive:
- Streptococcus
- Staphylococcus
- Gram negative:
- Escherichia coli
- Haemophilus influenzae and H. ducreyi
- Moraxella catarrhalis
- Salmonella
- Yersinia enterocolitica
- Shigella
- Campylobacter jejuni
- Vibrio cholerae
- Neisseria gonorrhoeae
- Helicobacter pylori
- Bordetella pertussis
- Atypical
- Mycoplasma pneumoniae
- Chlamydia pneumoniae
- Legionella pneumophila
- Treponema pallidum
- Babesia microti
- Ureaplasma
- Mycobacterium avium complex (MAC)
Types of infection
- Respiratory infections
- Community-acquired pneumonia
- MAC prophylaxis and treatment
- Legionnaire disease
- Pertussis
- Streptococcal pharyngitis
- Sexually transmitted infections
- Gonorrhea
- Chlamydia
- Chancroid
- H. pylori infection (clarithromycin is part of triple therapy)
- Skin and soft tissue infections (acne)
- Acne
Other indications
- Chronic obstructive pulmonary disease and cystic fibrosis exacerbations (anti-inflammatory effect)
- Gastroparesis (erythromycin, promotility effect)
Ketolide indications
- Similar antimicrobial activity as macrolides
- Telithromycin was discontinued in the United States (previously only indicated for community-acquired pneumonia).
Adverse Effects and Contraindications
Macrolides
- Adverse effects:
- GI upset (especially with erythromycin)
- Dizziness
- Hepatotoxicity
- Abnormal liver function tests
- Hepatitis
- Cholestatic jaundice
- Hepatic necrosis
- Hepatic failure
- QT prolongation
- Contraindications: history of hepatic impairment or cholestatic jaundice
- Warnings:
- Altered cardiac conduction (especially those with QT prolongation and electrolyte abnormalities)
- Hepatotoxicity
- Myasthenia gravis exacerbation
- Clarithromycin: potential ↑ mortality in patients with coronary artery disease
- Drug interactions (particularly with erythromycin and clarithromycin due to CYP3A4 inhibition):
- Warfarin: ↑ INR
- Simvastatin, lovastatin: ↑ risk of myalgia and/or rhabdomyolysis
- Midazolam: somnolence
- Theophylline: seizures
- ↑ Serum concentrations of:
- Tacrolimus
- Cyclosporine
- Ergot alkaloids
- Colchicine
Ketolides
- Adverse effects:
- GI upset
- Visual disturbance
- Hepatotoxicity
- Syncope
- Contraindications:
- Hypersensitivity to macrolide antibiotics
- Myasthenia gravis
- Hepatitis or jaundice
- Warnings:
- Hepatotoxicity
- Myasthenia gravis exacerbation
- QT prolongation
Mechanism of Resistance
There are 3 methods of resistance to macrolides:
- Ribosomal methylation or mutation:
- Prevents macrolide binding
- Can be either plasmid mediated or chromosomal
- Production of drug-inactivating enzymes:
- Esterases
- Kinases
- Production of active ATP-dependent efflux proteins:
- Transport the drug outside the cell
- Ketolides are not affected by this resistance mechanism → allows for their use in some macrolide-resistant strains
Comparison of Medications
| Drug class | Mechanism of action | Coverage | Adverse effects |
|---|---|---|---|
| Amphenicols |
|
|
|
| Lincosamides |
|
|
|
| Macrolides |
|
|
|
| Oxazolidinones |
| Gram-positive cocci:
|
|
VRE: vancomycin-resistant Enterococcus
Antibiotic sensitivity:
Chart comparing the microbial coverage of different antibiotics for gram-positive cocci, gram-negative bacilli, and anaerobes.
References
- Bertram G. (2007). Macrolide Antibiotics Comparison: Erythromycin, Clarithromycin, Azithromycin. Basic and Clinical Pharmacology. Retrieved March 5, 2021, from https://www.emedexpert.com/compare/macrolides.shtml.
- Tenson T, Lovmar M, Ehrenberg M (2003). The mechanism of action of macrolides, lincosamides and streptogramin B reveals the nascent peptide exit path in the ribosome. Journal of Molecular Biology. 330 (5): 1005–14. https://www.sciencedirect.com/science/article/abs/pii/S0022283603006624?via%3Dihub
- Leclercq, R. (2002). Mechanisms of resistance to macrolides and lincosamides: Nature of the resistance elements and their clinical implications. Clinical Infectious Diseases, 34(4):482-492. https://academic.oup.com/cid/article/34/4/482/412492
- Werth BJ. (2020). Macrolides. MSD Manual Professional Version. Retrieved June 29, 2021, from https://www.msdmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-drugs/macrolides
- Patel PH, Hashmi MF. (2021). Macrolides. StatPearls. Retrieved June 29, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK551495/
- Graziani, A.L. (2021). Azithromycin and clarithromycin. In Bond, S. (Ed.), UpToDate. Retrieved June 29, 2021, from https://www.uptodate.com/contents/azithromycin-and-clarithromycin
- Deck DH, Winston LG. (2012). Tetracyclines, macrolides, clindamycin, chloramphenicol, streptogramins, & oxazolidinones. In Katzung BG, Masters SB, Trevor AJ. (Eds.), Basic & Clinical Pharmacology (12th edition, pp. 809-819). https://pharmacomedicale.org/images/cnpm/CNPM_2016/katzung-pharmacology.pdf
