15 Macrolides, ketolides

Question 1

What are the macrolide drugs?

Answer 1

Question 2

What is the mechanism of action of macrolides?

Answer 2

• Protein synthesis inhibition
  
  • They irreversibly bind the 50S ribosomal subunit ==> inhibition of translocation of peptidyl-tRNA from acceptor to donor site
• Bacteriostatic
• Immunomodulatory effect

Question 3

What is the antibacterial spectrum of macrolides?

Resistance?

Answer 3

• Macrolides are wide-spectrum antibiotics
  
  • Gram (+) and gram (-) cocci (not MRSA)
  • Atypical organisms (Chlamydia, Mycoplasma, and Ureaplasma species)
  • Legionella pneumophila
  • Campylobacter jejuni
  • Bartonella
  • Bordetella
  • C. Diphteriae
  • Mycobacterium avium-intracellulare (MAC)
    
    • Only affects HIV patients
  • H. pylori
• No effect on gram (-) rods

Resistance:

• Inability of the organism to take up the antibiotic
• Efflux pump
• Reduced affinity of the 50S ribosomal subunit for the antibiotic
• Presence of a plasmid-associated erythromycin esterase in gram (-) bacteria (e.g. Enterobacteriaceae)

Question 4

What are the clinical uses of macrolides?

Answer 4

• Upper respiratory infections (atypical bacteria, penicillin allergy)
• STD
• Ulcer (clarithromycin)
• Skin infections
• Periodontal infections
• Diphtheria, pertussis
• Toxoplasmosis in pregnancy (spiramycin)
• Mycoplasma avium prophylaxis in AIDS patients (azithromycin)
• Can be used in pregnancy!!!

Question 5

What are the pharmacokinetics of macrolides?

Answer 5

• Oral administration (absorption of erythromycin is rather poor)
• Good distribution –> high concentration in cells
• Metabolism in the liver
• They inhibit cytochrome P450s ==> drug interactions!
  
  • Except Azithromycin (because it’s more soluble than the other macrolides)
• Effect is time-dependent

Administration:

• 3 days usage:
  
  • Erythromycin: 4x/day
  • Clarithromycin: 2x/day

Question 6

What are the side effects of macrolides?

Answer 6

• They stimulate motilin receptors and cause GI distress (Most marked with erythromycin)
• Reversible deafness at high doses
• Increased QT interval

Question 7

What are the ketolides?

Drugs?

Spectrum?

Indication?

…

Answer 7

Telithromycin:

• It belongs to the macrolide group, derived from erythromycin
  
  • They have a broader spectrum and are active against macrolide-resistant Strep pneumonia
    
    • This is possible by methylating the 50S ribosomal subunit bases
• Bactericidal

Spectrum:

• Like macrolides, but also against macrolide-resistant strains

Indication:

• Respiratory tract infections

Pharmacokinetics:

• Good absorption from GI
• Half-life: 9-10h
• Marked accumulation
• 1x/day administration

Adverse effects:

• GI symptoms
• Hepatotoxicity
• Visual disturbances
• CYP3A4 inhibition
• Neuromuscular blockade
• Contraindication:
  
  • Myasthenia gravis