Antibiotics: Protein synthesis inhibitors Flashcards
What are the classes of antibiotics that re protein synthesis inhibitors?
aminoglycosides, linezolid, tetracyclines, chloramphenicol/clindamycin, macrolides
What are the aminoglcycosides that I should know (or the relevant ending)?
gentamicin, tobramycin, neomycin, streptomycin
-mycin or -micin
Aminoglycoside MoA
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.
What antibiotics are often given synergistically and why?
- aminoglycosides and beta lactams or vancomycin:degradation of the cell wall promotes better aminoglycoside penetration.
- Sulfonamides and trimethoprims.
What is the most clinically important mechanism of resistance for aminoglycosides? Cross-resistance?
acquistion of drug-modifying enzymes that inactivate the drug. Not always cross-resistant: one enzyme may inactivate one aminoglycoside but not another.
What should I know about the pharmacokinetics of aminoglycosides? ADE. What should I know about kinetics and efficacy?
- 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)
What toxicities are associated with aminoglycosides?
ototoxicity, nephrotoxicity in a time- and concentration- dependent fashion.
give once daily dosing.
What, generally, is the activity of aminoglycosides?
broad gram-negative activity
gram-positive activity, esp. with a cell wall inhibitor
NO ACTIVITY AGAINST ANAEROBES
Tetracyclines MoA
reversibly bind 30S subunit and inhibit tRNA attachment.
Main MoR of tetracyclines?
efflux pumps
some proteins sequester the drug
resistance is VERY widespread
What toxicities are associated with tetracyclines?
discoloration of teeth and irregular bone growth in kids –> CONTRAINDICATED IN PREG. WOMEN AND CHILDREN.
Also very common to see superinfection with candida.
Tigecycline. uses, MoA
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.
What macrolides should I know/ending?
erythromycin, azithromycin, clarithromycin
=ROmycin
Macrolides: MoA
bind RNA of the 50S subunit and block translocation (growing peptide chain won’t move over so no new tRNA can come in)
Macrolides: MoR
methylation of drug-binding side on the 50S RNA or metabolism of the drug
What toxicities are associated with macrolides?
very few toxicities. potential for ototoxicity and hepatotoxicity. All bu azithromycin inhibit P450: CAREFUL with drug-drug interactions.
Fidaxomicin. MoA, use
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.
Chloramphenicol: MoA
binds 50S subunit. inhibits peptidyl transferase (both tRNAs bind, but you can’t attach the two amino acids to each other)
What toxicities are associated with chloramphenicol?
grey baby syndrome (baby turns cyanotic, then goes limp, then experiences cardiac collapse)
bone marrow suppression
drug interactions
toxicities limit clinical use of chloramphenicol
Clindamycin: MoA
like chloramphenicol. binds 50S subunit and inhibits penptidyl transferase.
How is clindamycin used?
severe infections caused by anaerobes; some staph and strep infections
Linezolid: MoA
binds rRNA of 50S ribosome and blocks formation of the initiation complex
Linezolid: MoR
mutation in rRNA
Linezolid: uses
MRSA and VRE skin and soft tissue infections
aerobic and anaerobic gram positive cocci and some gram positive rods
