7 – Aminoglycosides Flashcards

1
Q

Aminoglycosides structure

A
  • Lots of amino groups
  • **basic molecules
    o In more acidic pH=IONIZED
    o lots of + charges=may change distribution
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2
Q

**What are the NEED to know aminoglycosides in Vet Med?

A
  • Gentamicin
  • Amikacin
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3
Q

Gentamicin examples

A
  • Gentocin
  • Otomax, Mometamaxx, Easotic
  • Topagen
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4
Q

Gentocin

A
  • Sterile injectable solution (clear)
  • IM, SC or IU (intra-uterine in mares) on label
  • *often IV off-label
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5
Q

Otomax, Mometamaxx, Easotic

A
  • Topical ointments for otitis externa
  • *antibiotic, steroid and anti-fungal all together
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6
Q

Topagen

A
  • Topical spray for dermal lesions
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7
Q

Amikacin example

A
  • Amiglyde-V
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8
Q

Amiglyde-V

A
  • Sterile ‘injectable’ solution
  • *labelled only for IU use in mares
  • **often administered IV off label
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9
Q

(Neomycin)

A
  • 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)
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10
Q

(Apramycin)

A
  • Apralan oral solution for swine scours caused by E. coli
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11
Q

What is the mechanism of action of aminoglycosides?

A
  • Binds to bacterial ribosomal 30S sub-unit
    o Causes incorrect tRNA translation
    o Disrupts bacterial protein synthesis
    o Lead to increased bacterial membrane permeability
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12
Q

**Aminoglycosides need to penetrate bacterial cell to reach binding site: what is needed and what happens?

A
  • *need oxygen for the aminoglycosides to be taken up by the bacteria (OXYGEN DEPENDENT)
  • *if anaerobic environment=poor efficacy!
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13
Q

Local pH and aminoglycoside efficacy

A
  • Basic pH: non-ionized, easier to transport but can diffuse out
  • Acidic pH: more ionized, less transport in but, then ion-trapped
  • *unsure fully
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14
Q

Abscess and aminoglycoside efficacy

A
  • Does NOT work=cannot penetrate
    o Anaerobic!
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15
Q

What are aminoglycosides generally effective against?

A
  • *’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
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16
Q

What are aminoglycosides generally NOT or LESS effective against?

A
  • Less against Strep spp..
    o Especially amikacin
  • Intracellular pathogens
    o Salmonella
  • *anaerobes
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17
Q

Aminoglycosides: main resistance mechanism

A
  • *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
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18
Q

What are some other resistance mechanism against aminoglycosides?

A
  • Decrease permeability
  • Chromosomal resistance: NOT a big deal
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19
Q

Chromosomal resistance and aminoglycosides

A
  • Changes to 30S binding sites
  • Many 30S binding sites available, so these mutations don’t usually produce clinical resistance
20
Q

“First exposure adaptive resistance” - Decreased permeability and aminoglycoside resistance

A
  • 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
21
Q

Order of drugs: potency, spectrum of activity, stability against enzyme degradation (MORE to LEAST)

A
  • Amikacin: more potent spectrum against gram negative (but decrease gram positives, esp. Strep activity, DOES NOT MATTER)
  • Gentamicin
  • Neomycin
  • Streptomycin
22
Q

Oral bioavailability

A
  • Very poor
  • Historically found in calf scour boluses
  • Exception: some absorbed during enteritis or with high doses
    o Leave drug residues
23
Q

IM/SC injection bioavailability

A
  • Good absorption
  • *due to toxicity concerns=often give IV (EXTRALABEL)
24
Q

IU (label) or IMM (ELDU, cows, do NOT recommend) bioavailability

A
  • Some systemic absorption
25
Local delivery: bioavailability
- Hopefully MINIMAL absorption o Just want at the site
26
Volume of distribution, elimination time and route
- Low Vd - Rapid elimination (1-2hrs, first phase) o From plasma, but not ALL tissues - RENAL ELIMINATION
27
**Renal elimination
- Glomerular filtration - Renal disease=decreased GFR=decreased clearance o DOSE MODIFICATION SHOULD BE CONSIDERED - *binds to proximal tubule cells
28
**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)
29
What are the AE?
1. Nephrotoxicity 2. Ototoxicity 3. Neuromuscular blockade: rare 4. Drug interactions
30
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
31
What are some protective conditions to ‘avoid’ nephrotoxicity?
- *anything that can decrease contact of AG in filtrate with proximal tubule cells - 1. Increase GFR - 2. SID, high doses - 3. High calcium or protein in diet
32
Protective conditions: increase GFR
- FLUID THERAPY (hydration) - High protein in diet: not clinically useful
33
Protective conditions: SID, high dosing
- Rapid elimination in filtrate, so decrease overall contact
34
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
35
Ototoxicity (ear): AE mechanism
- same as nephrotoxicity - Likely not to notice this: but more of a problem LONG term
36
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
37
Neuromuscular blockade: AE
- Rare - Related to blockade of ACh at motor end plate - Treat with calcium
38
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
39
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
40
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
41
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
42
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
43
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
44
What about serum urea nitrogen and serum creatinine?
- NOT seen for 7 days o Damage is already done!
45
**What can you do when doing IV AGs to prevent toxicity and increase effectiveness?
- FLUIDS: safety - HIGH DOSE not very often (once a day)
46
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