Aminoglycosides

Background

• Derived from Streptomyces (mycins & kacins) or Micromonospora (micins)

Mechanism of Action

• Requires electron transport chain (ETC) to cross over the membrane
  • Anaerobes are therefore inherently resistant
• Reversibly binds 30S ribosomal subunit, which stops proofreading and causes accumulation of bad proteins

Spectrum of Activity

• Good coverage of Gram-negative aerobes
  • Except Stenotrophomonas and Burkholderia
• Streptomycin also covers mycobacterium
• Some protozoal coverage
• Can cover Gram-positives if cell wall is disrupted (e.g. by beta-lactam)

Mechanisms of Resistance

• Altered 50S ribosomal subunit
• Decreased uptake and accumulation (Pseudomonas)
• Decreased membrane permeability
• Efflux pump (Escherichia coli)
• Aminoglycoside-modifying enzymes (Enterococcus)

Pharmacokinetics and Pharmacodynamics

• Poor membrane penetration, therefore doesn't cross over into lungs and CSF
• Half-life 2-3 hours (longer in CKD)
• Excreted 99% unchanged in urine
• Displays concentration-depedent killing with a prolonged post-antibiotic effect (2-13 hours)

Dosing

Initial Dose

• If actual body weight more than 20% higher than ideal body weight, need to calculate adjusted body weight (ABW)

$$ABW = IBW + 0.4 \times (actual BW - IBW)$$

Traditional Dosing

• Q8H dosing
• Used for Enterococcus IE, meningitis, septic shock, ascites, AKI/CKD, pregnancy, surgical prophylaxis, burns, osteomyelitis
• 1.7 mg/kg (5-7.5 mg/kg amikacin) IV q8h

Extended Interval Dosing

• Q24H dosing, which is safer but less well-studied
• 7 mg/kg (15 mg/kg amikacin) IV, frequency depends on CrCl
  • CrCl ≥60 q24h
  • CrCl 40-59 q36h
  • CrCl 20-39 q48h
  • CrCl ≤19 don't use
• Use Hartford nomogram with a random level (but remember to halve the amikacin level first)

Dialysis Dosing

• Pre-HD levels with post-HD doses, though this may change

Synergy

• 1 mg/kg divided q8-12h, peak target 3-5, trough <2

Monitoring

Peak

• 30 minutes after third dose
• Response is based on peak:MIC ratio, target is 8-10 times
• If below target, increase dose

Trough

• Prior to 4th dose, or a random level at 24 to 48h in renal failure
• Side effects are predicted by trough levels
• Tobramycin <0.5 (extended) or <2 (traditional)
• Amikacin <1 (extended) or <?? (traditional)
• If above target, increase interval

Hartford Nomogram

• Dosing interval is whichever is the line just above the random level
• Double the concentration for amikacin

Safety

Adverse Drug Reactions

• Nephrotoxicity (0-50%), usually non-oliguric AKI with decreased Ca/Mg resorption, often reversible
  • Decreased protein synthesis
  • Decreased cellular respiration
  • Increased apoptosis
  • Necrosis in proximal tubules
• Ototoxicity (0-60%), irreversible
  • Cumulative effect
  • Distribute into the perilymph of the ear, and cause free radical formation causing apoptosis of hair cells
  • Needs hearing tests, because it can be subclinical
    • Monitor audiometry weekly
• Vestibulotoxicity (0-20%), irreversible
• Rarely, neuromuscular blockade

Monitoring

• Trough levels
• Creatinine
• Weekly audiometry