Macrolides and Ketolides

Macrolides and ketolides are antibiotics that inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit and blocking transpeptidation. These antibiotics have a broad spectrum of antimicrobial activity but are best known for their coverage of atypical microorganisms. Common macrolides are erythromycin, clarithromycin, and azithromycin. Side effects include GI upset, QT prolongation, and hepatotoxicity. Resistance mechanisms include ribosomal methylation or mutation, inactivation of the drug through enzyme production, or removal of the drug through efflux pumps.

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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

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

The site of action for macrolides on the 50S ribosomal subunit
tRNA: transfer RNA
mRNA: messenger RNA

Image by Lecturio. License: CC BY-NC-SA 4.0

Pharmacokinetics

Table: Pharmacokinetics of macrolides and ketolides
MacrolidesKetolides
AbsorptionErythromycin:
  • Destroyed by stomach acid → requires enteric coating
  • Relatively poor absorption
  • Food interferes with absorption
Azithromycin and clarithromycin:
  • Stable in the stomach
  • Better absorption
Rapid absorption
Distribution
  • Lipophilic
  • Widely distributed in body fluids and tissues
  • Uptake by macrophages:
    • Most notable in azithromycin
    • Contributes to a long half-life
  • Cross the placenta
  • Do not cross the blood-brain barrier
  • Widely distributed in tissues
  • 70% protein bound (albumin)
Metabolism
  • Hepatic
  • Clarithromycin and erythromycin: CYP3A4
  • Hepatic
  • CYP3A4
Excretion
  • Hepatic (bile → feces):
    • Azithromycin
    • Erythromycin
  • Renal: clarithromycin
  • Renal
  • Feces

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

Table: Comparison of several classes of bacterial protein synthesis inhibitor antibiotics
Drug classMechanism of actionCoverageAdverse effects
Amphenicols
  • Bind to the 50S subunit
  • Prevent transpeptidation
  • Gram positives
  • Gram negatives
  • Atypicals
  • GI upset
  • Optic neuritis
  • Aplastic anemia
  • Gray baby syndrome
Lincosamides
  • Bind to the 50S subunit
  • Prevent transpeptidation
  • Gram-positive cocci:
    • MSSA
    • MRSA
    • Streptococcus
  • Anaerobes
  • GI upset
  • Allergic reactions
  • Pseudomembranous colitis
Macrolides
  • Bind to the 50S subunit
  • Prevent transpeptidation
  • Gram positives
  • Gram negatives
  • Atypicals
  • Mycobacterium avium complex
  • GI upset
  • QT prolongation
  • Hepatotoxicity
  • Myasthenia gravis exacerbation
Oxazolidinones
  • Bind to the 23S rRNA of the 50S subunit
  • Prevent initiation complex formation
Gram-positive cocci:
  • MSSA
  • MRSA
  • VRE
  • Streptococcus
  • Myelosuppression
  • Neuropathy
  • Lactic acidosis
  • Serotonin syndrome
rRNA: ribosomal RNA
VRE: vancomycin-resistant Enterococcus
Antibiotic sensitivity chart

Antibiotic sensitivity:
Chart comparing the microbial coverage of different antibiotics for gram-positive cocci, gram-negative bacilli, and anaerobes.

Image by Lecturio. License: CC BY-NC-SA 4.0

References

  1. 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.
  2. 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
  3. 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
  4. 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
  5. Patel PH, Hashmi MF. (2021). Macrolides. StatPearls. Retrieved June 29, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK551495/
  6. 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
  7. 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

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