Aminoglycosides

Question 1

Are aminoglycosides ionized or non-ionized at physiological pH what does that mean?

Answer 1

ionized

- wont diffuse through cell membrane

Question 2

Name 3 common and 3 less used aminoglycosides

Answer 2

1. Gentamicin
   - gentocin (sterile injection, IM, AC, IU, IV
   - gentocin durafilm - ophthalmic solution
   - otomax & mometamaxx (topical for otitis externa)
   - topagem (spray for dermal)
2. Amikacin
   - amiglyde V (sterile injection, IU in mares, IV off label)
3. neomycin
   - calf scours boluses
   - panalog (topical ointment ofr otitis externa
4. apramycin (aminocyclitol)
   - apralan - oral for swine
5. streptomycin
   - calf/pig/poultry vitamin/antibiotic solution powder mixes
   - scours
6. dihydrostreptomycin

Question 3

What is the MOA of aminoglycosides?

Answer 3

binds to bacterial ribosomal 30s subunit
- incorrect tRNA tranlation, protein synthesis, increases membrane permeability

needs to penetrate bacterial cell to reach binding site

• oxygen dependent reaction between AG cation with - charges on bacterial membrane
• effect of local pH (basic is better)
• abscesses can inactivate AG

Question 4

What is the spectrum of activity of aminoglycosides?

Answer 4

very good at gram - (e.coli and pseudomonas
staph
enterococcus, mycobacteria, mycoplasma

less effective

• strep (amikacin)
• salmonella
• anaerobes (oxygen dependent interaction)

Question 5

What are the ways in which bacteria are resistant to AG?

Answer 5

plasma mediated enzymes (degrade AG and prevent binding to 30s)

• most significant for determining susceptability
• amikacin least susceptable

Decrease permeability (adaptive resistance)

chromosomal resistance

• changes to 30s
• so many binding sites it doesnt matter

First exposure resistance

• increase AG uptake by bacteria
• resistance accumulates within increased doses
• SID (hit em once and hard)

Question 6

what is the difference in potency, spectrum and resistance between the AG drugs?

Answer 6

amikacin > gentamicin > neomycin > streptomycin

• more potent, broader spectrum for gram - , low strep activity

Question 7

What is the F for AG?

Answer 7

poor oral F (except enteritis - high dose)

good IM/SC (toxicity so often given IV)

systemic absorption with IU or IMM
local is good

Question 8

What is the VD and elimination of AG?

Answer 8

VD - similar to b-lactams

rapid elimination

• glomerular
• renal disease decreases GFR and clearance
• binds to proximal tubules

Question 9

What is the PK-PD relationship of AG?

Answer 9

concentration dependent

• increase trough decreases adverse events
• long antibiotic effect (PAE)

Question 10

What dose regime is most rational for AGs?

Answer 10

high dose once a day

Question 11

Why do you want to “hit hard and hit it once” with AGs?

Answer 11

to avoid first resistance exposure
to maintain trough to reduce AEs
to reduce drug contact with proximal tubule cells

Question 12

What are the main adverse event of AG use? what is its mechanism?

Answer 12

nephrotoxicity (acute tubular necrosis)
Mechanism:
uptake and accumulation of AG into renal proximal tubule
- AG cation binds to - charge on tubular cells
- enters via marrier mediated pinocytosis
- sequestered in lysosomes
- builds up, bursts, cell death

proximal tubule important for reabsorbing all things

Question 13

What is the protective mechanism to nephrotoxicity?

Answer 13

minimize drug interaction with proximal tubule

• increase GFR (hydration)
• high dose rather than small ones (cant all bind)
• high calcium or protein (compete)

Question 14

What are other AE of AGs?

Answer 14

ototoxicity

• same mechanism
• both ototoxicity adn nephro exacerbated with diuresis (dehydration)

neuromuscualr blockage

• rare (anesthesia)
• black ach at motor end plate
• treat with calcium

Drug interaction

• pH abnormalities
• synergism with b-lactams
• avoid other drugs

drug residues

• neomycin
• gentamycin

Question 15

Why is systemic use of AG not good?

Answer 15

takes a long time to eliminate from kidney

Question 16

What is therapeutic drug monitoring?

Answer 16

can measure T1/2

measuring peak and trough

Question 17

how else can you monitor nephrotoxicity?

Answer 17

increase urine gamma glutamyl tasference (GTT) enzyme and urine (GTT:crreatinine) ratio

• UGGT:UCr may go up within 3d
• high dose infrequent
• oral works because not good F and less nephrotoxicity

proteinuria

increase in serum urea nitrogen and serum creatinine (not seen for 7d)

Question 18

How can you increase effectiveness, decrease nephrotoxicity and decrease resistance for IV gentamycin and amikacin?

Answer 18

IV fluid therpay (flush it out)

infrequent high doses (SID or less)

Question 19

What is local drug therapy? how does it help?

Answer 19

regional perfusion (IVRP) or intraosseous
intraarticular
antimicrobial impregnanted beads (PMMA)- slow dissolve
- problems with resistance with long periods below MIC

decrease toxicity and resistance