Antibiotics: Protein synthesis inhibitors

Question 1

What are the classes of antibiotics that re protein synthesis inhibitors?

Answer 1

aminoglycosides, linezolid, tetracyclines, chloramphenicol/clindamycin, macrolides

Question 2

What are the aminoglcycosides that I should know (or the relevant ending)?

Answer 2

gentamicin, tobramycin, neomycin, streptomycin

-mycin or -micin

Question 3

Aminoglycoside MoA

Answer 3

irreversibly bind 30S ribosomal subunit and prevent initiation complex formation. Crosses the outermembrane of gram negative bacteria through porins. Requires OXYGEN DEPENDENT transport across inner membrane.

Question 4

What antibiotics are often given synergistically and why?

Answer 4

1. aminoglycosides and beta lactams or vancomycin:degradation of the cell wall promotes better aminoglycoside penetration.
2. Sulfonamides and trimethoprims.

Question 5

What is the most clinically important mechanism of resistance for aminoglycosides? Cross-resistance?

Answer 5

acquistion of drug-modifying enzymes that inactivate the drug. Not always cross-resistant: one enzyme may inactivate one aminoglycoside but not another.

Question 6

What should I know about the pharmacokinetics of aminoglycosides? ADE. What should I know about kinetics and efficacy?

Answer 6

• poor oral absorption and tissue distribution
• cleared by kidneys
• concentration-dependent killing, but significant killing even after the drug is undetectable in the serum. Give by once-daily dosing to limit toxicities (benefits: a large spike to give dose-dependent kill, but less time with toxic concentrations in the blood)

Question 7

What toxicities are associated with aminoglycosides?

Answer 7

ototoxicity, nephrotoxicity in a time- and concentration- dependent fashion.
give once daily dosing.

Question 8

What, generally, is the activity of aminoglycosides?

Answer 8

broad gram-negative activity
gram-positive activity, esp. with a cell wall inhibitor
NO ACTIVITY AGAINST ANAEROBES

Question 9

Tetracyclines MoA

Answer 9

reversibly bind 30S subunit and inhibit tRNA attachment.

Question 10

Main MoR of tetracyclines?

Answer 10

efflux pumps
some proteins sequester the drug
resistance is VERY widespread

Question 11

What toxicities are associated with tetracyclines?

Answer 11

discoloration of teeth and irregular bone growth in kids –> CONTRAINDICATED IN PREG. WOMEN AND CHILDREN.
Also very common to see superinfection with candida.

Question 12

Tigecycline. uses, MoA

Answer 12

this is a relatively new tetracycline (2005) with activity against MRSA, VRSA, VRE, and many tetracycline-resistant bacteria because it does not bind to the efflux pumps that inactivate other tetracyclines.

Question 13

What macrolides should I know/ending?

Answer 13

erythromycin, azithromycin, clarithromycin

=ROmycin

Question 14

Macrolides: MoA

Answer 14

bind RNA of the 50S subunit and block translocation (growing peptide chain won’t move over so no new tRNA can come in)

Question 15

Macrolides: MoR

Answer 15

methylation of drug-binding side on the 50S RNA or metabolism of the drug

Question 16

What toxicities are associated with macrolides?

Answer 16

very few toxicities. potential for ototoxicity and hepatotoxicity. All bu azithromycin inhibit P450: CAREFUL with drug-drug interactions.

Question 17

Fidaxomicin. MoA, use

Answer 17

structurally related to macrolides but functionally distinct: Inhibit RNA pol
good for C difficile infection- poorly absorbed from GI tract; little activity against normal intestinal flora.

Question 18

Chloramphenicol: MoA

Answer 18

binds 50S subunit. inhibits peptidyl transferase (both tRNAs bind, but you can’t attach the two amino acids to each other)

Question 19

What toxicities are associated with chloramphenicol?

Answer 19

grey baby syndrome (baby turns cyanotic, then goes limp, then experiences cardiac collapse)
bone marrow suppression
drug interactions
toxicities limit clinical use of chloramphenicol

Question 20

Clindamycin: MoA

Answer 20

like chloramphenicol. binds 50S subunit and inhibits penptidyl transferase.

Question 21

How is clindamycin used?

Answer 21

severe infections caused by anaerobes; some staph and strep infections

Question 22

Linezolid: MoA

Answer 22

binds rRNA of 50S ribosome and blocks formation of the initiation complex

Question 23

Linezolid: MoR

Answer 23

mutation in rRNA

Question 24

Linezolid: uses

Answer 24

MRSA and VRE skin and soft tissue infections

aerobic and anaerobic gram positive cocci and some gram positive rods