Aminoglycosides Flashcards Preview

Pharm test #3 > Aminoglycosides > Flashcards

Flashcards in Aminoglycosides Deck (31):
1

what are the common aminoglycosides

Gentamicin
Tobramycin
amikacin
streptomycin

2

how do aminoglycosides work

Irreversibly bind to 30S ribosomal subunit of susceptible bacteria resulting in inhibition of protein synthesis
Cell entry is oxygen-dependent

3

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

4

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

5

what would you use to treat enterococcus (gram +)

gentamicin + ampicillin (or another pcn or vancomycin)

6

Spectrum of Activity 
Tobramycin

Gram-negative

Similar to gentamicin BUT
More active against Pseudomonas**

Slightly less active against other gram-negatives

7

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

8

what to use when treating Pseudomonas with an aminoglycoside

Tobramycin

9

Spectrum of Activity 
Streptomycin

Gram-positive
Enterococcus

Mycobacterial
M. tuberculosis
Less atypical mycobacteria than amikacin

mainly used for Enterococcus if gentamicin cannot be used

10

aminoglycosides and synergy

• Synergy between cell wall active agents and AGs
• Likely due to enhanced AG uptake

11

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

12

aminoglycoside elimination

99% renally eliminated (urine conc ~ 50-100x serum conc)
30-40% removed by hemodialysis
Linear PK - doubling the dose doubles the concentration

13

Pharmacodynamics

• Concentration-dependent killing
• PK/PD parameter: peak/MIC (goal ≥ 8 – 10) higher = more optimal efficacy

14

Postantibiotic Effect

Persistent suppression of bacterial growth after drug concentration falls below the MIC of targeted organism

wide range of aminoglycosides

15

Postantibiotic Effect is impacted by


Organism
Drug concentration
Duration of drug exposure
Antimicrobial combinations

16

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

17

Dosing 
Amikacin for gram negative

doses are 2-3x what you would give for gentamicin or tobramycin.

may use traditional or extended interval

18

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

19

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)

20

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

21

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

22

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

23

ways to decrease nephrotoxicity

give higher doses less frequently
make sure to get a low trough level to give kidney time without drug

24

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

25

how does extended interval dosing save money

Decreased pharmacy preparation time

Decreased nursing administration time

Potentially decreased drug concentration monitoring

26

Clinical Uses of aminoglycoids for gram negative infections

• gent, tobra, amikacin
• In combination with beta-lactams to treat resistant and/or serious infections
• Empiric treatment of sepsis, especially from a urinary source
• Bloodstream, intraabdominal infections, skin/soft tissue infections
• Need to use high dose if giving for pneumonia
• Rarely used as monotherapy

27

clinical uses of aminoglycoids for gram positive infections

• mostly gent, some strepto
• In combination with beta-lactams (ampicillin or nafcillin) or vancomycin for severe infections (enterococcal or staphylococcal endocarditis)
• High peak concentrations are NOT necessary so low dose is sufficient

28

aminoglycoid use for mycobacteria infections

• amikacin, streptomycin
• In combination with multiple antimycobacterial agents

29

risk factors for nephrotoxicities

prolonged/repeditive use, *elevated trough concentrations, prolonged therapy, underlying renal insufficiency, advanced age, hypovolemia, concomitant nephrotoxins

Gent > tobra > amik > strepto

30

Ototoxicity risk factors

Usually irreversible (may appear after the end of treatment)

Risk factors: increased age, prolonged AG course, ?increased serum concentrations, ?genetic factors -- not as well understood

31

best way to enhance efficacy and minimize toxicity

get in and get out

optimize the Peak/MIC ratio by giving high but infrequent doses