Macrolides

Question 1

What is the mechanism of action for macrolides?

Answer 1

• Macrolides inhibit bacterial protein synthesis by binding reversibly to the P site of the bacterial ribosome.
• This inhibits the translocation of peptidyl-tRNA from the A site to the P site.
• primarily bacteriostatic

Question 2

What drug is this?

Answer 2

erythromycin

• desosamine sugar is important for activity (upper right)

Question 3

Why do macrolide antibiotics have methyl groups on alternative carbon atoms?

Answer 3

• they are produced by sequential addition of propionate groups to a growing chain
• this results in methyl groups on alternate carbon atoms in the macrolide ring

Question 4

What are the mechanisms of resistance to macrolide abx?

Answer 4

1. lactone ester hydrolase
2. drug-induced production of an RNA methylase
3. mutation of adenine to guanine at A2058
4. efflux pump

• degrades the macrolides by breaking cyclic structure
• A2058 gets methylated which inhibits the binding of macrolides to the 50S subunit
• mutation reduces binding
• efflux pump ejects drugs from cell

Question 5

Why is resistance to macrolide abx by pseudomonas spp. and enterobacter spp. unavoidable?

Answer 5

• They exhibit intrinsic resistance
• There are specific genes in the organisms that confer this resistance

Question 6

How can acidic conditions inactivate erythromycin?

Answer 6

• the 6-OH and 12-OH get involved in acid-catalyzed ketal formation
• this is why oral erythromycin has to be administered as enteric coated tablets or as stable salts or estsers

Question 7

How can acid stability of erythromycin be achieved?

Answer 7

• 6-OCH derivative –> blocks ketal formation at low pH
  or
• replace C-9 ketone with N-methylated methyleneamino moiety –> blocks ketal formation

Question 8

If part of erythromycin was replaced with this, what drug would it be?

Answer 8

• clarithromycin
• replaces 6-OH with OCH3 to stabilize at low pH

Question 9

If part of erythromycin was replaced with this, what drug would it be?

Answer 9

• azithromycin
• replaces C-9 ketone to prevent ketal formation

Question 10

How is erythromycin metabolized?

Answer 10

Erythromycin undergoes demethylation in the liver.

Demethylation leads to narrower spectrum and less active

Question 11

Which macrolides are likely to have drug interactions due to binding and inhibiting CYP3A?

Answer 11

• erythromycin
• clarithromycin

Azithromycin does NOT inhibit CYP3A, which makes it safer

Question 12

What is the spectrum of activity for macrolides?

Answer 12

Gram-positive

Question 13

What are the clinical uses for macrolides?

Answer 13

• URTI
• pertussis
• chlamydia

Question 14

What are the main side effects of macrolides?

Answer 14

• GI effects
• gastric cramps
• allergic reactions
• long term use –> reversible cholestatic hepatitis

Long-term use is 10-20 days

Question 15

Why does clarithromycin produce less gastric cramping than erythromycin?

Answer 15

More acid stable –> less irritating products (ketals) are formed

Question 16

What role do phagocytes have in the delivery of erythromycin to the site of action?

Answer 16

• erythromycin is rapidly absorbed and diffuses into most tissues and phagocytes
• due to the high concentration in phagocytes, erythromycin is actively transported to the site of infection
• during active phagocytosis, large concentrations of erythromycin are released

Question 17

Why is azithromycin acid stable while erythromycin is not?

Answer 17

Azithromycin has a 15-membered lactone ring, eliminating the hydroxyl group that participates in ketal formation.