Objectives:

Describe process of protein synthesis (review)

Describe/explain the mechanism of action for the agents discussed
Compare/contrast antibiotic characteristics:
structural
pharmacokinetic
Recognize several of the primary therapeutics indications/uses for the
agents discussed
For the agents discussed, identify and recognize:
Spectrum of antibacterial activity
Route(s) of administration & dosing considerations
ADRs
Mechanisms of resistance
Aminoglycosides - Examples
Gentamicin
Tobramycin
Amikacin
Neomycin
Other - Streptomycin / Paromomycin
MOA: exact not fully known
Protein synthesis inhibitors
interfere with proofreading process, increasing rate of error in synthesis with premature
termination
inhibition of ribosomal translocation where peptidyl-tRNA moves from A site to P site
disrupts the integrity of the bacterial cell membrane
blocks initiation of protein synthesis
incorporation of incorrect amino acid (missed insertion)
Mechanisms of Resistance
Enzymatic - inactivation due to AAC (acetyltransferases), ANT (nucleotidyltransferases or
adenyltransferases) , and APH (phosphotransferases)
Transport - absence or alteration in transport system, inadequate membrane potential,
modification in LPS phenotype can result in cross resistance
Ribosomal - alteration, single step mutations in chromosomal genes encoding ribosomal
proteins
Pharmacokinetics
A - gent/tob/ami poor oral bioavailability
D - stays in the plasma
Aminoglycosides
M
E - excreted renally
Administration
Route - parenteral most common, inhalation (tobi) and oral (neo)
Regimen -
Traditional: above toxicity threshold 20 hrs, q8 and q12, renal dosing adjustment
nephrotoxicity: kidney
ototoxicity: hearing loss and ear pain
vestibulartoxicity: balance
Once Daily AG: under threshold over 50% of the time (preferred)
Terms / Concepts
Concentration-dependent killing:
dependent upon concentration achieved
inc conc. inc killing
Time-dependent killing:
continuous infusion
more time spent over MIC, inc killing
Post Antibiotic Effect
concentration-dependent killing
continues to kill when below MIC
Kill Curves
higher drug rate, faster kill
Combination Effect
Indifference: not much extra killing with A+B
Synergy: work together for significant kill
Antagonism: one drug antagonizes other
Peak: MIC Ratios
10 or higher: likelihood of treatment success
Antimicrobial Spectrum
Gram- rods
examples:
pseudomonas
entero
shigella
klebsiella
serratia
E. coli
Aminoglycosides
Adverse Effects
nephrotoxicity: dose adjusted renally (CrCl)
ototoxicity: ears, pain, hearing loss, ringing (can be reversed)
vestibulotoxicity: dizziness, vertigo, balance
renal toxicity: dangerous with combination of AG and another nephrotoxic drug
Aminoglycosides