L3 Pharm: Aminoglycosides Flashcards
What is the mechanism of action of Aminoglycosides?
Why are aminoglycosides inefficient against anaerobic bacteria?
What does the pneumonic: “mean” GNATS caNNOT kill anaerobes help remind us?
What type of bacteria (generally speaking) do AG’s target?
Inhibit protein synthesis by binding to 30s ribosomal subunit.
Cell entry is oxygen dependent. (need energy from oxygen)
GNATS G- gentamicin N- neomycin A - amikacin T - tobramysin S - streptomysin
cause:
N- nephrotoxicity
N - NeuroMuscular block
O - ototoxicity
T - teratogen
TARGET GRAM NEGATIVE AEROBES!
(enterics)
Are aminoglycosides bacteriostatic or cidal?
How?
What type of bacteria are they used for primarily (general category)?
Bacteriostatic
- IRREVERSIBLE inhibition of initiation complex through binding of the 30s subunit
- cause misreading of mRNA
(also block translocation)
- Gram negative RODS
What is the mechanism of resistance for Aminoglycosides? (3)
- Bacterial TRANSFERASE enzymes inactivate the drug by
- acetylation
- phosphorylation
- Adenylation
(plasmid mediated via one bacteria to another) - Alter aminoglycoside uptake
- loss of porin channel
- efflux pump
(chromosomal mutation that influence binding/EC gradient that influences uptake) - Alteration in ribosomal binding site/target modification
- RARE for gentamicin, tobramycin, amikacin (mostly strep)
What is the pneumonic
” buy AT 30, CCEL (sell) at 50”
30 s inhibitors::
A- aminoglycosides
T - tetracycline
50s inhibitors:
C- chloramphenicol
C - chlindamycin
(bacteriostatic for bothC)
E - erythromycin (macrolides) (bacterostatic)
L - linezolid
What gram negative bacteria does Gentamicin target?
(8)
It is the least active against what gram - bacteria?
- E. coli
- K. pneumoniae
- Proteus
- Citrobacter
- Enterobacter
- Morganella
- Serratia
- Pseudomonas
(ALL ARE ENTEROBACTERIACIAE!!! enterics)
- targets all the ones that stain pink on MacConkey
(macConKEE’S agar)
** very poor activity against gram neg. compared to other AG’s**
- Least active against pseudomonas
What gram positive bacteria does Gentamicin target?
(used the most for gram positive, ALWAYS in combo w/ aminopenicillins)
- Enterococcus
- S. aureus
- Viridans Streptococcus
- S. pyogenes
What gram negative bacteria does TOBRAMYCIN target?
Similar to Gentamicin:
BUT:
1. More active against PSEUDOMONAS
- Slightly less active against other gram neg. compared to Gentamicin
(especially the enterics!)
Pseudomonas:
gent = 88%
Tobramycin = 92% susceptible
TOBRA & GENT have similar activity for gram -!
What TYPE of gram negative bacteria is Amikacin most active against?
WHat 2 other bacteria does it cover? (atypical/anaerobe)
- MOST active against NOSOCOMIAl gram negatives
(except vs. Tobra for pseudomonas) - a) M. Tuberculosis
b) Nocardia
What is the MAIN gram positive bacteria STREPTOMYCIN targets?
T/F: Streptomycin has higher activity than Amikasin for M. Tuberculosis
ENTEROCCOCUS
(but, only use this if cannot use Gentamicin!)
FALSE: it has LESS activity
Synergy exists between ____ and Aminoglycosides.
What is synergy?
Cell wall active agents (B-lactams & vancomycin)
The effect of drugs in combination is greater than the anticipated results based on the effect of each individual drug (the effects are MORE than additive)
BEST WAYS TO MINIMIZE RESISTANCE = kill the bug quickly (do not want bacteriostatic growth like with vancomycin by itself
- want less development of resistance so add AMINOGLYCOSIDE)
ESPECIALLY FOR SERIOUS INFECTIONS like endocarditis
What 3 bacteria are targeted by the following synergistic combinations?
- AMpicillin, Pen, Vancomysin (gent or strep)
- B- Lactams + Vancomycin (gent)
- B - Lactams + AG (gent, tobra, amikacin)
- Enterococcus
- S. aureus
- P. Aeriginosa
Aminoglycoside PK’s
- Poor ____ absorption
- Well absorbed after ____
- What is the preferred route of admin?
- Tobramycin is given how?
- Poor ORAL absorption
- IM admin shows good absorption
- IV!!!
- Inhalation
Aminoglycoside PK’s:
- low/high protein binding?
- low/high water solubility?
- Distributes low in ____
High in ____ - Eliminated how?
- LOW protein binding
(Vd represents EC space) - HIGH water solubility
- MINIMAL CSF penetration
High URINE concentrations
- Eliminated RENALLy (GFR)
- high urine conc. can lead to nephrotoxicity
Aminoglycoside PK’s:
- What kind of killing?
- Peak/MIC goal?
- PAE ranges from what?
- What determines EFFICACY for AGs?
- how is this different than for Penicillins?
- CONCENTRATION dependent killing
- Peak/MIC > 8-10
- Post - Antibiotic effect (suppression of bacterial growth after drug conc. falls below MIC)
= 0.5 - 7.5 hrs - EFFICACY = Peak:MIC
- DO NOT CARE ABOUT HOW LARGE THE AUC: MIC is - Penicillins : all we wanted was TIME ABOVE THE MIC (did not care about the peak)
BUT FOR AMINOGLYCOSIDES WE WANT A HIGH PEAK!!!
HIGHER THE PEAK = longer the post-antibiotic effect
(penicillins & B-lactams have limited post-antibiotic effect)
What do the following factors influence:
- Organism
- Drug concentration
- Duration of drug exposure
- Antimicrobial combinations
Factors that impact PAE
Persistent suppression of bacterial growth after drug concentration falls below the MIC of targeted organism
PAE range for AGs: 0.5 – 7.5h
What is the traditional dosing for Gent & Tobramycin used for gram negative infections? (peak?)
Extended interval dosing? (peak?)
- 2 – 2.5 mg/kg q8h for normal renal function
Goal levels: peak 5-10
- Extended (once daily)
- 5-7 mg/kg/once daily
- want a LOW trough (undetectable)
- but LARGER PEAK
State the difference between traditional vs. Extended interval dosing.
What is the main rationale for 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
CONCENTRATION DEPENDENT BACTERICIDAL activity
also: Post-antibiotic effect (PAE) Adaptive resistance – occurs when bacteria continously exposed to antibiotic Minimize toxicities Nephrotoxicity Ototoxicity Cost savings Efficacy
GRAPH: - suggested peak /mic ratio of at least 8-10
Nephrotoxicity due to AG is related to what?
Uptake of AGs into proximal tubule is ____ at clinical achieved concentrations.
- Intracellular accumulation of drug in RENAL CORTEX
- SATURABLE
Animal studies have shown that continuous infusion AG results in higher renal cortical concentrations compared with a single daily injection regimen
– trough concentration & extended persistent exposure is what leads to NEPHROTOXICITY
How is nephrotoxicity manifested as?
T/F: Nephrotoxicity is reversible
What is the main risk factor in terms of PK parameters?
What is the most nephrotoxic of the following; the least?
- Tobramycin
- Gentamycin
- Streptomycin
- Amikacin
(arrange in order)
- Non-oliguric AZOTEMIA (buildup of N2 containing compound) secondary to PT damage
- increase in BUN &Cr - TRUE NEPHROTOXICITY is reversible
- adjust AG dose
- discontinue drug early - PROLONGED HIGH TROUGH CONCENTRATIONS
- also therapy >2 weeks
Gentamicin> Tobramycin>amikacin>streptomycin
Ototoxicity (auditory & vestibular) is due to damage of what CN?
T/F: Ototoxicity is reversible
Auditory toxicity common with which drugs? (list 3)
Vestibular toxicity? (4)
- CN 8
- FALSE: it is IRREVERSIBLE
- auditory toxicity:
amikacin>gentamicin>tobramicin - Vestibular:
streptomycin > gentamicin > amikacin >tobramycin
Sparse data for risk of ototoxicity based on dosing regimen
- severe damage may occur with normal concentrations and/or may be related to total drug exposure
Which relies more on dosing regimen: ototoxicity or nephrotoxicity?
NEPHROTOXICITY (reversible)
- NO DIFFERENCE IN OTOTOXICITY
What are some benefits of once daily dosing?
Decreased pharmacy preparation time
Decreased nursing administration time
Potentially decreased drug concentration monitoring
5/9 studies found improved response rates with patients who received HIGHER DOSES
AG’s used in comb with beta-lactams to treat ____ and other highly resistant gram negative bacilli.
Often used for ___ especially from a URINARY source.
1 . Pseudomonas Aeruginosa
- hypermetabolic so give a large dose & then give another dose if it is undetectable in 8 hours
(careful with burn patients since fluid overloaded)
- SEPSIS
Need to use high dose if giving for pneumonia
Rarely used as mono therapy (except for UTI)
T/F: High doses of AMinoglycosides are used for both gram neg. & gram positive infections
FALSE
- high only for gram negative
High peak concentrations are NOT necessary for gram positive (give low dose)
Gram-positive infections (mostly gent, some strepto)
In combination with beta-lactams (ampicillin or nafcillin) or vancomycin for severe infections (enterococcal or staphylococcal endocarditis)
What AG is most likely to cause nephrotoxicity?
What is the main risk factor that leads to nephrotoxicity?
Gentamicin
AG-induced renal tubular necrosis is reversible
- prolonged elevated trough concentrations**
(TEST)
**if renal function is worsening but gram negative in blood
- evaluate risk/benefit
- benefit to give HIGH DOSE and put them on dialysis so that they can survive
OtoToxicity may occur before what?
What is the main risk?
2nd?
BEFORE SYMPTOMS appear
- increased age,
- prolonged AG course
What is the AG of choice for Pseudomonas??
Tobramycin!!!
