Aminoglycosides Flashcards
what are the common aminoglycosides
Gentamicin
Tobramycin
amikacin
streptomycin
how do aminoglycosides work
Irreversibly bind to 30S ribosomal subunit of susceptible bacteria resulting in inhibition of protein synthesis
Cell entry is oxygen-dependent
mechanisms of resistance to aminoglycosides
• Synthesis of AG modifying enzymes
Plasmid-mediated
>50 AG altering enzymes
Cause acetyl-, adenyl-, or phosphorylation
these changes usually result in altered uptake or binding
• Altered AG uptake
Loss of porin channel
Efflux pump
• Change in ribosomal binding site/target modification
gentamicin spectrum of activity
Gram-negative E. coli K. pneumoniae Proteus Citrobacter Enterobacter Morganella Serratia Pseudomonas
Gram-positive Enterococcus S. aureus Viridans Streptococcus S. pyogenes
very good gram negative, has the best synergy for enterococcus treatment
least pseudomonas activity of the aminoglycosides
what would you use to treat enterococcus (gram +)
gentamicin + ampicillin (or another pcn or vancomycin)
Spectrum of Activity Tobramycin
Gram-negative
Similar to gentamicin BUT
More active against Pseudomonas**
Slightly less active against other gram-negatives
Spectrum of Activity Amikacin
Gram-negative
Generally, most active against nosocomial gram-negatives (except vs tobra for Pseudomonas, most of the time)
Mycobacterial
M. tuberculosis
Atypical mycobacteria
Others
Nocardia
used as a broad spectrum 2nd choice empiric therapy
what to use when treating Pseudomonas with an aminoglycoside
Tobramycin
Spectrum of Activity Streptomycin
Gram-positive
Enterococcus
Mycobacterial
M. tuberculosis
Less atypical mycobacteria than amikacin
mainly used for Enterococcus if gentamicin cannot be used
aminoglycosides and synergy
- Synergy between cell wall active agents and AGs
* Likely due to enhanced AG uptake
aminoglycoside distribution
- Low in CSF, bronchial secretions, bile (30%), vitreous humor (40%)
- high/good Pleural, pericardial, ascitic, and synovial fluid ~50% of serum
- High in urine
aminoglycoside elimination
99% renally eliminated (urine conc ~ 50-100x serum conc)
30-40% removed by hemodialysis
Linear PK - doubling the dose doubles the concentration
Pharmacodynamics
- Concentration-dependent killing
* PK/PD parameter: peak/MIC (goal ≥ 8 – 10) higher = more optimal efficacy
Postantibiotic Effect
Persistent suppression of bacterial growth after drug concentration falls below the MIC of targeted organism
wide range of aminoglycosides
Postantibiotic Effect is impacted by
Organism
Drug concentration
Duration of drug exposure
Antimicrobial combinations
Dosing Gentamicin and Tobramycin for a gram negative infection
Traditional : doses give 3x a day or every 8 hours - keeps a more constant low level of drug present
extended interval (once a day) dosing : give one large dose per day - higher peak lower trough
Dosing Amikacin for gram negative
doses are 2-3x what you would give for gentamicin or tobramycin.
may use traditional or extended interval
Dosing for Gram-positive infections
use either gentamicin or streptomycin, gram positive bacteria are killed time dependently therefore multiple smaller and more frequent doses are given
Dosing Mycobacterial infections
Amikacin/streptomycin given in high doses (higher than for gram negative) once a day or less but over a much longer time period (months)
Traditional vs. Extended-Interval Dosing
Traditional dosing (MDD) Approximately same daily dose given every 8 to 12 hours
Extended-interval dosing (ODA)
One large dose given at an interval no less than every 24 hours
Rationale for Extended-Interval Dosing
Concentration-dependent bactericidal activity Post-antibiotic effect (PAE) Adaptive resistance - may become less resistant during off time Minimize toxicities Nephrotoxicity Ototoxicity Cost savings Efficacy
Nephrotoxicity of aminoglycoids
- Related to intracellular accumulation of drug in the renal cortex
- Uptake of AGs into proximal tubule cells is saturable at clinically achieved concentrations
- Animal studies have shown that continuous infusion AG results in higher renal cortical concentrations compared with a single daily injection regimen – thought to be due to the amount accumulated over time not peak concentration
- REVERSIBLE
ways to decrease nephrotoxicity
give higher doses less frequently
make sure to get a low trough level to give kidney time without drug
Ototoxicity with aminoglycoids
- Uptake of AGs into different inner ear tissues does not correlate with the degree of ototoxicity
- Sparse data for risk of ototoxicity based on dosing regimen
- does not seem to correlate with any dosing perimeter
