177: Aminoglycosides Flashcards
Are aminoglycosides concentration or time-dependent?
concentration dependent
Describe the mechanism of action of aminoglycosides
bactericidal
* penetrates bacterial cell wall and membranes
* binds to the 30s ribosomal subunit
* misreading of mRNA ==> production of nonfunctional proteins, detachment of ribosomes from mRNA, cell death
What is the spectrum of aminoglycosides?
mostly gram-negative aerobes
some gram-positives
no anaerobes
why do aminoglycosides not work against anaerobic bacteria?
uptake across bacterial cell wall depends on energy derived from aerobic metabolism
will not work at low pH or O2 tension environments, e.g.
Should aminoglycosides be considered for animals with abscesses and why
no
will not work at low pH or O2 tension environments, e.g., abscesses
What antibiotic group can you combine aminogylcosides with to create synergism and enhanced efficacy, and why
beta-lactams
* increase cell permeability
* increases the uptake of aminoglycosides into bacteria
Which has a broader antimicrobial spectrum, gentamicin, or amikacin
amikacin
perferred agent for very resistant microbials
Why is monotherapy with an aminoglycoside not appropriate in critically ill animals?
- want synergistic efficacy
- want other antimicrobial to provide coverage during amino-glycoside free intervals in SDD protocol
- need to combine with metronidazole or clindamycin for strict anaerobic pathogens
How is the oral bioavailability of aminoglycosides, and what conditions may change this?
poor bioavailabilirty
may have significant systemic absorption and toxicity in conditions causing compromised intestinal epithelial barrier
What are 3 criteria your patient should fulfill before starting aminoglycoside therapy?
- adequate hydration
- stable renal function
- inactive urine sediment
Do aminoglycosides have a high or low volume of distribution, and how does this affect tissue penetration?
highly water soluble with small volume of distribution
poor penetration of biologic membranes
e.g., CSF, prostate, vitreous humor not well penetrated
How are aminoglycosides mainly excreted?
through glomerular filtration
< 5% reabsorbed in the tubules
In what tissues do aminoglycosides achieve therapeutic concentrations?
- pleural fluid (nonexudative)
- peritoneal fluid
- bones
- synovial fluid
- pulmonary parenchyma (not bronchial secretion)
What dosing interval should be used for aminoglycosides. Give 3 reasons for it.
single daily dosing protocol
reasons:
* concentration dependent antibiotic
* overcome adaptive resistance
* decreased incidence of toxicities, i.e., mainly nephrotoxicities
What is adaptive resistance?
first exposure effect –> down-regulated aminoglycoside uptake by bacteria
* subsequent doses have lower bactericidal effect and shorter postantibiotic effect
* can be prevented by giving subsequent doses after adaptive resistance has passed, i.e., SDD
What measurements need to be taken for therapeutic drug monitoring and at what time should they be taken?
- peak-level blood sample 20-30 min after IV administration
- trough-level blood sample 2-4 hours before next dose
Which measurement, peak or trough level correlates with adverse reactions?
trough concentrations
want at least 2-4 hours of drug free intervals
Name examples for conditions leading to increased volume of distribution
- vascular leakage
- edetamous states
- hypoalbuminemia
- hyperdynamic states from SIRS
- mechanical ventilation
- extensive burn injuries
- severe trauma
may lead to subtherapeutic serum levels
What is the recommended starting dose for gentamicin?
6-10 mg/kg q24h
start with low end in cats
recommended starting dose for amikacin
10-15 mg/kg q24h
start with low end in cats
why may IM/SC administration undesirable compared to IV
- associated with discomfort
- less predictable absorption
can you give aminoglycosides through same line/catheter as LRS?
No, don’t give with solutions containing Ca
also not with NaHCO3- or heparin
Can you give aminoglycosides together with penicillins in the same syringe?
No
inactivates aminoglycosides
What are the 3 main toxicities caused by aminoglycosides?
toxicity to:
* neuromuscular junction
* inner ear apparatus
* kidneys
Where in the kidneys do aminoglycosides cause damage?
proximal convoluted tubules
How do you treat an animal suffering from weakness due to aminoglycoside administration. How commonly do you expect to see this in practice?
- injectable Ca
- not common, weakness appears at dosages higher than recommended
at risk: animals already suffering from neuromuscular disorders
What is the mechanism of action behind ototoxicity by aminoglycosides?
accumulates in the cochlear and vestibular apparatus and destroys sensory hair cells
related to duration of treatment, not dose, but not established in SA
True or false, aminoglycosides cause anuric kidney failure
False, polyuric kidney injury
describe how aminoglycosides lead to renal insufficiency
- aminoglycosides have a cationic state ==> will bind to tubular epithelial cells and transported IC via lysosomes
- lysosomes destabilize and rupture
- disrupts normal cell structure and function
- results in decline in glomerular filtration
At what day of administration do aminoglycosides have maximum tubular toxicity?
around day 9 of therapy
Which one is more nephrotoxic, gentamicin or amikacin?
gentamicin
Why does SDD lead to less nephrotoxicity?
uptake of aminoglycosides by tubules appears to be saturable
* less uptake with high but infrequent dosages compared to lower frequent dosages
What is more nephrotoxic, amikacin in the morning or at night?
at night
circadian rhyhtm may lead to decreased GFR during the night ==> higher incidence of toxicities
this needs more investigation in veterinary medicine
true or false, we should measure a renal panel daily to check for aminoglycoside induced renal insufficiency?
false, late stage insensitive marker
What is the most sensitive marker of aminoglycoside induced renal damage?
enzymuria
unfortunately not very practical
How do you asses for aminoglycoside induced renal damage?
check urine sediment daily for granular or cellular casts
check urine for glucosuria and tubular proteinuria
What are risk factors for aminoglycoside induced renal damage?
- older age
- duration of therapy
- fever
- volume depletion or dehydration
- administration of other nephrotoxic drugs
- preexisting renal disease
- K or Mg depletion
