7 – Aminoglycosides Flashcards
Aminoglycosides structure
- Lots of amino groups
- **basic molecules
o In more acidic pH=IONIZED
o lots of + charges=may change distribution
**What are the NEED to know aminoglycosides in Vet Med?
- Gentamicin
- Amikacin
Gentamicin examples
- Gentocin
- Otomax, Mometamaxx, Easotic
- Topagen
Gentocin
- Sterile injectable solution (clear)
- IM, SC or IU (intra-uterine in mares) on label
- *often IV off-label
Otomax, Mometamaxx, Easotic
- Topical ointments for otitis externa
- *antibiotic, steroid and anti-fungal all together
Topagen
- Topical spray for dermal lesions
Amikacin example
- Amiglyde-V
Amiglyde-V
- Sterile ‘injectable’ solution
- *labelled only for IU use in mares
- **often administered IV off label
(Neomycin)
- Used to be big in vet med
- Various calf scour boluses
- Skin and ear ointments
- Antimicrobial “preservative” in many vaccines (to ensure NO infection of the vaccine itself)
(Apramycin)
- Apralan oral solution for swine scours caused by E. coli
What is the mechanism of action of aminoglycosides?
- Binds to bacterial ribosomal 30S sub-unit
o Causes incorrect tRNA translation
o Disrupts bacterial protein synthesis
o Lead to increased bacterial membrane permeability
**Aminoglycosides need to penetrate bacterial cell to reach binding site: what is needed and what happens?
- *need oxygen for the aminoglycosides to be taken up by the bacteria (OXYGEN DEPENDENT)
- *if anaerobic environment=poor efficacy!
Local pH and aminoglycoside efficacy
- Basic pH: non-ionized, easier to transport but can diffuse out
- Acidic pH: more ionized, less transport in but, then ion-trapped
- *unsure fully
Abscess and aminoglycoside efficacy
- Does NOT work=cannot penetrate
o Anaerobic!
What are aminoglycosides generally effective against?
- *’opposite of penicillin
- **Very good against gram NEGATIVE aerobic bacteria
o Especially enteric bacteria
o *Pseudomonas - Good against Staph
o Including some MRSA/MRSP - Some activity against Enterococcus, mycobacteria and mycoplasma
What are aminoglycosides generally NOT or LESS effective against?
- Less against Strep spp..
o Especially amikacin - Intracellular pathogens
o Salmonella - *anaerobes
Aminoglycosides: main resistance mechanism
- *plasma-mediated enzymes degrade them and PREVENT BINDING to ribosome 30S subunit
o **most significant for determining clinical susceptibility
o Amikacin is LEAST affected by these enzymes
What are some other resistance mechanism against aminoglycosides?
- Decrease permeability
- Chromosomal resistance: NOT a big deal
Chromosomal resistance and aminoglycosides
- Changes to 30S binding sites
- Many 30S binding sites available, so these mutations don’t usually produce clinical resistance
“First exposure adaptive resistance” - Decreased permeability and aminoglycoside resistance
- Due to decreased uptake (permeability) by bacteria
- Occurs within 1-2h of dose
- Lasts up to 16h post-exposure
o Then partial return of susceptibility - *resistance accumulates with increasing number of doses
- IMPLICATION: use ONCE DAILY dosing with HIGH concentrations to decrease adaptive resistance effect
Order of drugs: potency, spectrum of activity, stability against enzyme degradation (MORE to LEAST)
- Amikacin: more potent spectrum against gram negative (but decrease gram positives, esp. Strep activity, DOES NOT MATTER)
- Gentamicin
- Neomycin
- Streptomycin
Oral bioavailability
- Very poor
- Historically found in calf scour boluses
- Exception: some absorbed during enteritis or with high doses
o Leave drug residues
IM/SC injection bioavailability
- Good absorption
- *due to toxicity concerns=often give IV (EXTRALABEL)
IU (label) or IMM (ELDU, cows, do NOT recommend) bioavailability
- Some systemic absorption
Local delivery: bioavailability
- Hopefully MINIMAL absorption
o Just want at the site
Volume of distribution, elimination time and route
- Low Vd
- Rapid elimination (1-2hrs, first phase)
o From plasma, but not ALL tissues - RENAL ELIMINATION
**Renal elimination
- Glomerular filtration
- Renal disease=decreased GFR=decreased clearance
o DOSE MODIFICATION SHOULD BE CONSIDERED - *binds to proximal tubule cells
**Concentration-dependent antimicrobial
- Cmax : MIC >10
- **Increase TROUGH (rather than increase peak) plasma concentration correlates with AE
o If trough higher=more AE - Long post-antibiotic effect
- CLINICAL IMPLICATION: high dose, but only SID (or less)
What are the AE?
- Nephrotoxicity
- Ototoxicity
- Neuromuscular blockade: rare
- Drug interactions
Nephrotoxicity (acute tubular necrosis): mechanism of AE
- Most common
- *uptake and accumulation of AG into renal proximal tubule cells
o AG binds to charged phosphotidylinositol on tubular cells
o AG enters cell via carrier-mediated pinocytosis
o AG sequestered in lysosomes=eventually ruptures
o Causes cell death
What are some protective conditions to ‘avoid’ nephrotoxicity?
- *anything that can decrease contact of AG in filtrate with proximal tubule cells
- Increase GFR
- SID, high doses
- High calcium or protein in diet
Protective conditions: increase GFR
- FLUID THERAPY (hydration)
- High protein in diet: not clinically useful
Protective conditions: SID, high dosing
- Rapid elimination in filtrate, so decrease overall contact
Protective conditions: high calcium or protein in diet
- Cations compete with + charges on AG for tubule cell binding
- *likely not relevant due to feeding time required
Ototoxicity (ear): AE mechanism
- same as nephrotoxicity
- Likely not to notice this: but more of a problem LONG term
Why are nephron and ototoxicity exacerbated by diuretics?
- Good for getting things out of kidney, but then animal is losing urine and may be DEHYDRATED for a period of time afterwards
- Want to use a FLUID BAG
Neuromuscular blockade: AE
- Rare
- Related to blockade of ACh at motor end plate
- Treat with calcium
Drug interactions: AE
- pH incompatibilities (mixed together in syringe)
o NOT usually mixing things in same syringe=NOT a problem
o ONE drug, ONE syringe - “synergy” with beta-lactams (but IN VITRO only)
- Avoid using with other nephrotoxic drugs
Beta-lactam and AG ‘synergism’
- Only IN VITRO
- *complementary spectrum but not because they make each other work better
- *humans: higher incidences of AE (nephrotoxicity)
- *more if you have a severe condition and not sure what is happening=combo or broad spectrum is justifiable
AG use and food animals
- Drug residues can occur
- Extremely SLOW depletion from the kidney (pretty much the rest of their life)
- Neomycin and Gentamicin residue violations are COMMON
o Not as much a problem now, as they are used as much anymore in food animals - Plasma: 1 day
- Urine: 100 days
- Kidneys: high even 1 year later
- *do NOT use extra label use in food animals
Therapeutic drug monitoring: when worried about dosing regimen
- Need a human lab with an assay (need peak and trough plasma concentrations)
- Increase urine gamma glutamyl transferase (GGT) enzyme and urine [GTT:creatinine] ratio
- Proteinuria
- Increase in serum urea nitrogen and serum creatinine
Look at urine enzyme levels and compare to urine creatinine levels (GGT:creatinine ratio)
- Creatinine: base line marker of FILTRATION
- UGGT : UCr may go up 2-3x baseline within three days of a nephrotoxic dose
- *most SENSITIVE: can find in a couple of days
Proteinuria for therapeutic drug monitoring
- Disadvantages
o Lots of things cause it
o Takes time for it to occur=likely TOO late and probably already finished therapy
What about serum urea nitrogen and serum creatinine?
- NOT seen for 7 days
o Damage is already done!
**What can you do when doing IV AGs to prevent toxicity and increase effectiveness?
- FLUIDS: safety
- HIGH DOSE not very often (once a day)
Local drug therapy
- Regional perfusion
o IVRP or intra-osseous
o Intra-articular (joint injections: gentamycin)
o *hopefully have exposed the site to high doses - Antimicrobial-impregnated beads (polymethylmetacrylate, PMMA)
o ‘double-edged’ sword: high concentration at injection site, but slowly leaks out=prolonged exposure
