Aminoglycosides Flashcards
What are the core structures of AMGs?
- streptidine
- 2-Deoxystreptamine
What is the mechanism of action for the AMGs?
- AMGs inhibit protein synthesis by binding to the 30S ribosomal subunit
- Within 30S, they bind to 16S rRNA - A site
- cause frameshift
- This interferes with formation of initiation complex, blocks translation, and elicits premature termination
- Causes impairment of proofreading function –> nonsense proteins –> impaired bacterial wall
- Ultimately lead to leakage of ions and disruption of cytoplasmic membrane –> cell death
What are the mechanisms of AMG uptake?
- Initial entry of positively charged AMGs through the outer membrane involves displacement of Mg- and Ca- ions that form salt bridges with phosphates of the phospholipids in the membrane. This makes the membrane more permeable to the AMGs
- Passage through the cytoplasmic membrane is an active transport process
What are the three resistance mechanisms for AMGs?
- metabolism
- altered ribosomes
- altered AMG uptake
- bacteria inactivate the AMGs
- binding site gets altered through point mutations
What is the toxicity profile of AMGs?
- irreversible ototoxicity
- reversible nephrotoxicity
- reversible curare-like effects (neuromuscular paralysis) from large doses
- likelihood of toxicity increases with treatment period
- more effective and less toxic alternatives exist –> use those instead
What are the symptoms of AMG ototoxicity?
- tinnitus
- high-frequency hearing loss
- vestibular damage
vestibular damage = vertigo, loss of balance, ataxia
Which AMG toxicities are reversible?
- nephrotoxicity
- respiratory paralysis
Which drugs potentiate the nephrotoxicity of AMGs?
- loop diuretics
- vancomycin
- amphotericin
How can the respiratory paralysis from AMGs be reversed?
- neostigmine or calcium gluconate
- mechanical respiratory assistance may be necessary
What are the risk factors for AMG toxicity?
- longer treatment period (> 5 days)
- elderly
- impaired renal fx
- higher dose
How can AMG toxicity be minimized?
- use sparingly
- monitor serum concentrations
What are the therapeutic uses of AMGs?
Almost always reserved for tx of gram-negative bacteria
Why do pcns and AMGs need to be administered at different sites?
- pcns interact with amine on AMGs which inactivates both abx
- formation of covalent adducts
Why is amikacin less susceptible to bacterial metabolism than kanamycin?
- The presence of the L-hydroxyaminobuteryl amide moiety inhibits bacterial metabolism by R-factors
What is amikacin used for?
- mycobacterium tuberculosis
- AMG-resistant nosocomial infections
