aminoglycosides Flashcards
aminoglycosides used in vet med
- Gentamicin:
– GentocinVM - sterile injectable solution - IM, SC, IU routes on label (but commonly administered IV off-label)
– OtomaxVM, MometamaxxVM, Easotic - Topical ointments for otitis externa
– TopagenVM – topical spray for dermal lesions - Amikacin:
– Amiglyde-VVM – sterile “injectable” solution - Labelled only for IU use in mares (but often administered IV off-label
** best potency and broader spectrum agaisnt gram - but decreased strep activity.
aminoglycoside structure
-lots of amino groups
-very basic molecules so at a physiological pH will be in its IONIZED form.
-antimicrobial name ends in MYCIN
Aminoglycosides:
Mechanism of Action
- Binds to bacterial ribosomal 30S sub-unit
– Causes incorrect tRNA translation
– Disrupts bacterial protein synthesis
– Lead to ↑ bacterial membrane permeability
-Needs to penetrate bacterial cell to reach binding site:
– oxygen-dependent interaction.
DONT DO WELL IN ANAROBIC ENVIRO
– Abscesses: purulent material can inactivate AG
Local pH: any impact aminoglycoside efficacy?
- Basic pH: AG non-ionized, easier transport in but can diffuse out?
- Acidic pH: AG more ionized, less transport in but then ion-trapped?
-not much clinical efficacy
Aminoglycosides: Spectrum of Activity
Very good against Gram (-)
aerobic bacteria
– Many Gram (-) enteric bacteria
– Including Pseudomonas**
- Good activity against Staph spp.
– Including some MRSA/MRSP - Some activity against
Enterococcus, mycobacteria,
mycoplasma
– In vitro more than clinical?
Generally NOT/LESS effective:
* Less activity against Strep. spp.
– Especially amikacin
* Intracellular pathogens
– Salmonella (variable activity)
* Anaeroebes
aminoglycosides spectrum short form
-gram - including psuedomonas
-some gram + incl. staph but less against strep
-NOT ANAROBES
-concentration dependent antimicrobial
aminoglycoside resistance
-
Plasmid-mediated enzymes that degrade AG and prevent binding to ribosome 30S subunit
– Most significant for determining clinical susceptibility
– Amikacin is least affected by these enzymes** - ↓ permeability (adaptive resistance )
- Chromosomal resistance: not a big deal here, tons of binding sites to bind to.
aminoglycoside first exposure resistance
“First exposure adaptive resistance”
– Due to ↓ AG uptake (permeability) by bacteria
– Occurs within 1 - 2 h of dose
– Lasts up to 16 h post-exposure
* Then partial return of susceptibility
– Resistance accumulates with increasing # of doses
– IMPLICATION:
* Use once-daily dosing to ↓ adaptive resistance effect
-Want to dose low frequency at a high concentration to decrease first exposure adaptive resistance.
Pharmacokinetics of aminoglycosides absorption
Bioavailability by route:
* Oral: Very poor bioavailability
– Yet found in calf scour boluses! due to leaky gut in calves.
– Exception: some absorbed during enteritis or with high doses
* Good absorption after IM/SC injection
– But due to toxicity concerns, often given IV (extralabel)
- Some systemic absorption with IU (label) or IMM (ELDU) doses
- Local delivery: hopefully minimal absorption (more later)
PK of aminoglycosides
- Low Vd (similar to β-lactams)
- Rapid elimination (T1/2 elim = 1 -2 h)
– Rapidly depletes from plasma…but not all tissues! - Elimination route: RENAL
– Eliminated by Glomerular filtration
– Renal disease = ↓ GFR = ↓ clearance of AG - DOSE MODIFICATION SHOULD BE CONSIDERED
– Binds to proximal tubule cells!
aminoglycoside PK-PD
concentration-dependent antimicrobial!
* Cmax : MIC > 10
* ↑ trough (rather than ↑ peak) plasma concentration
correlates with adverse events
– More later
* Long post-antibiotic effect
* Clinical Implication:
– Give High dose, but only SID (or less)
-steeper kill curve if given at higher dose.
Adverse Events of Aminoglycosides
- Nephrotoxicity (Acute tubular necrosis)
* Most common ADR with aminoglycosides
* Mechanism: Uptake and accumulation of AG into
renal proximal tubule cells, causes cell death
-ototoxicity: both are exacerbated by diuretics
-neuromuscular blockade (treat with Ca+)
-drug interactions: pH incompatibilities, synergism with b-lactams
how to protect against aminoglycoside AE
Anything that ↓ contact of aminoglycoside in filtrate with
the proximal tubule cells will protect the nephron:
* ↑ GFR
– Fluid therapy (hydration)
– High protein in diet (not really)
* SID, high dosing (vs multiple smaller doses)
– Rapid elimination in filtrate, so ↓ overall contact
* DEMONSTRATION TIME!
* High calcium or protein in diet
– Cations compete with (+) charges on AG for tubule cell binding (dont use really)
-just hydrate and dose.
Aminoglycoside Use
in Food Animals
Drug residues can occur
* Extremely slow depletion from the kidney (binding to prox tubule)
* Neomycin, Gentamicin residue violations are common
therapeutic drug monitoring for aminoglycosides
Peak: 0.5 - 1 hr after dose (depends on route)
Trough: measure 8 hr after dose if dosing q 24 hr
- ↑ urine gamma glutamyl transferase (GGT)
enzyme & urine [GGT:creatinine] ratio, will go up 2/3x with a nephtotoxic dose. good way to measure** - Proteinuria
– Advantages / disadvantages? - ↑ serum urea nitrogen & serum
creatinine:
Not seen for 7 days (damage already done)
