Antibacterials - Vancomycin

Question 1

Vancomycin is a …

Answer 1

nonribosomal glycopeptide antibiotic produced by fermentation of Nocardia orientalis

Question 2

Mode of action of Vancomycin

Answer 2

inhibitor of gram+ cell wall biosynthesis

Vancomycin is cup shaped. It binds the peptidyl side chain D-ala-D-ala, preventing the transpeptidase reaction that is required for cross-linking

Question 3

Spectrum of activity of vancomycin

Answer 3

Primarily bactericidal and is active against Gram+ bacteria

Essentially all gram- bacilli and mycobacteria are not susceptible to vancomycin

Question 4

What is the mechanism of resistance to vancomycin?

Answer 4

A mutation of the peptidoglycan cell wall precursor from D-ala-D-ala to D-ala-D-lactate. Vancomycin does not inhibit the transpeptidase when the substrate is D-ala-D-lactate because its affinity for this compound is 1000 times less.

Question 5

What are the toxicity and side effects of vancomycin?

Answer 5

1. hypersensitivity - red skin rash and potential anaphylaxis
2. nephrotoxicity and ototoxicity

Question 6

Important points about the structure and biosynthesis of macrolides

Answer 6

1. Macrolide antibiotics are macrocyclic lactones. Usually 14 membered lactone rings
2. Unusual deoxyhexose sugars are essential for biological activity
3. They are polyketides b/c 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.
4. The pKa of the amine in erythromycin is 8.8. The amine can form salts that are more soluble.

Question 7

Mechanism of action of macrolides

Answer 7

Inhibit bacterial protein synthesis by binding reversibly to the P side of the bacterial ribosome, thereby inhibiting translocation of peptidyl-tRNA from the A site to the P site

Question 8

How do macrolides get transported to the site of infection?

Answer 8

Macrolides tend to accumulate within leukocytes

Question 9

Four basic mechanism of resistance to macrolides

Answer 9

1. Lactone ester hydrolase induced to degrade the macrolides by hydrolysis of the macrocycle
2. Drug-induced production of an RNA methyl’s. This inhibits the binding of macrolides to the 50S subunit
3. Mutation of the adenine to duanine at the specific site A2058. 10,000 fold reduction in binding to 23 S ribosomal RNA
4. Efflux pump ejects drugs from the cell by an active transport process

Question 10

Erythromycin chemical reactivity with acid

What does this mean for erythromycin administration?

Answer 10

Inactivated under acidic conditions by a process involving the 6-OH group

The reaction is an intramolecular acid-catalyzed ketal formation. The metal reaction product is inactive.

Oral erythromycin is admin as enteric coated tables or as more stable salts or esters

Question 11

The main route of erythromycin metabolism is …

The main route of elimination is …

Erythromycin’s half-life is …

Answer 11

demethylation in the liver (metabolism)

In the bile, and a small portion in the urine (elimination)

1.5 hours

Question 12

Drug interactions

• Erythromycin and clarithromycin bind and inhibit …
• Generally, reactivity of other drugs metabolized by the same CYP are … , except … which is …

Answer 12

Bind and inhibit CYP3A

Activities of drugs than an interaction is expected with are increased due to inhibition of their metabolism
EXCEPT in the case of rifampicin and rifabutin, where the activity of erythromycin is reduced

Question 13

Side effects of macrolides

Answer 13

1. Strongly stimulate GI motor activity and can cause vomiting, gastric cramps, and abdominal pain
2. Allergic skin rxns. Steven-Johnson syndrome and toxic epidermal necrolysis are serious side eefcts that are rare but may occur
3. Long term use can induce a reversible cholestatic hepatitis which will manifest as jaundice with cramping/nausea/fever
4. Increases probability of pyloric stenosis in children whose mothers took the drug during the late stages of pregnancy or while nursing

Question 14

General comments on pharmacokinetics of erythromycin

Answer 14

• inactivate by all gastric acids – need to admin as coated capsule or as more stable salts
• very rapidly absorbed and diffuses into most tissues and phagocytes
• actively transported to site of infection, where during active phagocytosis, large concentration of erythromycin are released

Question 15

Erythromycin estolate

Answer 15

1. Propronyl ester, lauryl sulfate prodrug of erythromycin
2. Propionyl ester makes the drug more lipophilic and increases oral absorption
3. Contraindicated in patients with preexisting liver disease or dysfxn
4. Used to treatm GABHS, syphillus, and used prophylactically prior to surgery to prevent endocarditis by strep viridins

Question 16

Erythromycin ethyl succinate

Answer 16

1. Prodrug
2. Ethyl succinate ester makes the drug more lipophilic and increase absorption after oral administration
3. Used as a flavored oral suspension in pediatric pts

Question 17

Clarithromycin

Answer 17

1. Increased stability in acidic conditions (blocks ketal formation)
2. Better oral absorption
3. Less gastric upset
4. 14-R-hydroxy metabolite of clarithromycin has greater antibiotic activity than clarithrymycin itself
5. available as oral suspicion, tables, and extended-release tablets

Question 18

Azithromycin

Answer 18

1. 15 membered ring
2. More stable to acid in the stomach
3. Terminal half life of 68 hours
4. Mg and Al (in some antacids) form coordinate complexes w/ azithromycin and prevent absorption
5. biliary excretion is the major route of elimination
6. Greater activity against G- than erythromycin or clarithromycin
7. Most common side effects are GI