Macrolides

Question 1

What is the polyketide biosynthesis pathway?

Answer 1

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

Question 2

What is the mechanism of action of macrolides

Answer 2

• bind reversibly to the P site of the bacterial ribosome, inhibiting translocation of peptidyl-tRNA from the A site to the P site and obstruct peptide bond formation (bind to 23S RNA, not the protein)

Question 3

How is the solubility of erythromycin increased

Answer 3

COOH group

Question 4

What are the four basic mechanisms of resistance of macrolides

Answer 4

• lactone ester hydrolase degrade macrolides by hydrolysis of the macrolide (breaking up the COOH group)
• drug induced production of RNA methylase (A2058 mutation on the 23S RNA is methylated inhibiting binding to the 50S subunit)
• mutation of adenine to guanine at the specific site A2058 (10,000 fold reduction of binding of erythromycin and clarithromycin)
• an efflux pump by active transport

Question 5

How can you reduce macrolide resistance

Answer 5

• reduce use of macrolides unless indciated

Question 6

Why cant resistance to pseudomonas and enterobacter be avoided

Answer 6

they have intrinsic resistance by not allwoing entry of these drugs

Question 7

In what conditions are macrolides inactivated?

Answer 7

• acidic conditions
• intermolecuolar acid catalyzed ketal formation where the ketal formation product is inactive
• need oral enteric coated tablets for erythromycin

Question 8

How can acid stability be achieved?

Answer 8

• 6-OCH derivative in clarithromycin

Question 9

Why is azithromycin staable in acid

Answer 9

• N-methylated methylaeneamino moity replaces the C9 ketone, so ketaal formation is no longer possible

Question 10

Whaat is the metabolism of erythromycin

Answer 10

demethylation in the liver

Question 11

Drug interactions

Answer 11

• inhibit cyp3a and p450 isozymes
• not really azithromycin

Question 12

What is the spectrum of activity for erythromycin

Answer 12

skin and soft tissue infections caused by gram positive bacteria

Question 13

Bugs treated with erythromycins

Answer 13

• mycoplasma pneumoniae infections
• GAS URI
• legionella infection
• bordetella pertussis
• campylobacter jejuni
• corynebacterium

Question 14

Disease states treated with erythromycins

Answer 14

• bacterial bronchitis
• otitis media
• acne
• sinusistis
• pelvic inflammatory disease

Question 15

Side effects

Answer 15

• strongly stimulate gastrointestinal motor activity (vomiting, gastric cramps, abdominal pain)
• minor and severe allergic reactions
• reversible cholestatic hep wit hlong term use
• pyloric stenosisi n children durign lactation

Question 16

What role do phagocytes have in delivery of erythromycin

Answer 16

• erythromycin is very rapidly absorbed and diffuses into most tissues and phagocytes
• due to high concentrations of phagocytes, erythromycin is actively transported to the site of infection
• very effective drug delivery