Infectious diseases: Pharmacology - Aminoglycosides

Question 1

Four examples of aminoglycosides

Answer 1

Gentamicin
Tobramycin
Amikacin
Streptomycin

Question 2

Mechanism of action of aminoglycosides

Answer 2

Bind irreversibly to ribosomal 30S subunit to inhibit bacterial protein synthesis

Question 3

Coverage of aminoglycosides

Answer 3

Mostly for aerobic Gram negatives

Question 4

What type of bacteria are not targeted by aminoglycosides and why?

Answer 4

Anaerobes, as aminoglycosides rely on O2-dependent transport mechanisms to enter bacterial cytoplasm

Question 5

Indications for aminoglycoside use

Answer 5

Gram negative enterics
Mostly used in combination with beta lactams (use with other B-lactams adds Gram positive coverage and acts synergistically)

Question 6

Why are aminoglycosides typically used in combination with beta-lactams?

Answer 6

Combination gives good Gram positive and negative coverage
Beta-lactams increase permeability of bacterial cell wall to aminoglycosides

Question 7

Two mechanisms of resistance to aminoglycosides

Answer 7

1. Production of inactivating transferase enzymes
2. Impaired cell entry

Question 8

Describe the pharmacokinetics of aminoglycosides

Answer 8

Absorption: very poor oral absorption, good IM absorption but generally given IV
Distribution: rapid distribution, does not reach eye or CNS (but can be given intra-thecal)
Metabolism: not metabolised, t1/2 2-3hrs, narrow therapeutic index
Excretion: renally cleared (needs dose adjustment in renal impairment)

Question 9

Give two reasons why aminoglycosides are best administered in a single large once-daily dose instead of smaller multiple doses

Answer 9

1. Aminoglycosides demonstrate concentration-dependent killing (increased concentration of drug increases both the proportion and rate of bactericidal activity) and postantibiotic effect (antibacterial effect persists beyond the time in which measurable drug is present), both of which are optimised with large single dose
2. Toxic effects are time- and concentration-dependent: after concentration threshold is met, time spent beyond this threshold increases risk of toxicity (less time spent above threshold with large single dose)

Question 10

Three adverse effects of aminoglycosides

Answer 10

1. Ototoxicity
2. Nephrotoxicity
3. Neuromuscular blockade at high doses

Question 11

Does the ototoxicity seen with aminoglycoside use impact auditory or vestibular function?

Answer 11

Both/either

Question 12

Four factors which increase risk of aminoglycoside-associated ototoxicity and nephrotoxicity

Answer 12

1. Elderly
2. Renal impairment
3. Therapy >5 days
4. Higher doses

Question 13

What other factors may increase risk of nephrotoxicity with aminoglyoside use?

Answer 13

1. Elderly
2. Renal impairment
3. Therapy >5 days
4. Higher doses
5. Use of loop diuretics or other nephrotoxics

Question 14

How can the curare-like effects seen with high doses of aminoglycoside be reversed?

Answer 14

Calcium gluconate