IID 15: Aminoglycosides Flashcards
Describe the absorption of aminoglycosides.
poorly absorbed orally
Describe the distribution of aminoglycosides.
Vd = 0.2-0.3 L/kg
How does Vd and clearance change with:
- Neonates
- Pediatric
- Pregnancy
- Critically Ill
- Renal Impairment
- Cystic Fibrosis
- Burns
- neonates: ↑ Vd, ↓ clearance
- pediatric: Vd normalized to adult with age, ↑ clearance
- pregnancy: ↑ Vd, ↑ clearance
- critically ill: ↑ Vd, ↓ clearance
- renal impairment: ↓ clearance
- cystic fibrosis: ↑ Vd, ↑ clearance
- burns: ↑ Vd, ↑ clearance
Describe the metabolism of aminoglycosides.
not metabolized
Describe the elimination of aminoglycosides.
t1/2 = 2-3 hr
- eliminated via glomerular filtration as unchanged drug
Describe the pharmacodynamics of aminoglycosides.
- bactericidal
- concentration-dependent killing
- post-antibiotic effect (0.5-10 hr) depends on bacterial strain and minimum inhibitory concentration (MIC), duration of exposure, concentration of aminoglycoside
- Cmax:MIC ≥ 8:1 to 10:1 necessary to optimize bactericidal activity and avoid bacterial regrowth
- Cmax:MIC ≥ 10:1 may prevent emergence of aminoglycoside-resistant pathogens
What dosing weight is used to calculate aminoglycoside doses?
- use actual body weight (ABW) unless patient is obese
- use dosing body weight (DBW) if patient is obese (> 25% over IBW)
- DBW = IBW + 0.4 (ABW - IBW)
What should aminoglycoside doses be rounded to?
nearest 10 mg (in adults)
How long should aminoglycoside doses be infused over?
30 mins
What is the rationale for extended interval dosing?
- optimizes concentration-dependent killing effects
- takes advantage of post-antibiotic effect
- proposed to cause less nephrotoxicity as it provides period where aminoglycosides could leach out of tubular epithelium
- less frequent drug administration
- prevents adaptive resistance (?)
- ↓ costs (less levels, drug administration costs) (?)
What patients are excluded from extended interval dosing?
- patients with burns to > 20% of BSA
- patients with ascites
- pregnant women
- patients with end-stage renal disease (including dialysis)
- synergy for treatment of infective endocarditis (?)
Extended Interval vs. Conventional (Multiple Daily) Dosing
in general, extended interval dosing appears to be similar efficacy to conventional, but no consistent reduction in toxicities
When is Cpk and Ctr drawn in conventional dosing?
- Cpk drawn ≥ 30 min after end of 30 min infusion
- Ctr drawn within 30 min prior to next dose
Specific target Cpk should be individualized for patient using what clinical factors?
- site of infection
- severity of infection
- treatment vs. prophylaxis
- primary treatment vs. synergistic agent
- organism and MIC
When are no levels required?
patients < 60 years with normal body weight, stable renal function (CrCl ≥ 60 mL/min), and short course of therapy (< 7 days)
- ie. healthy patient receiving extended interval dosing
When are steady-state pre/trough (Ctr) and post/peak (Cpk) levels required?
(draw 3rd or later maintenance dose)
- extended duration of therapy (> 7 days)
- infections requiring higher Cpk
- patient factors that make PK parameter less predictable (burn, CF, amputee, quadriplegia)
- patients at risk of toxicity (ie. on concurrent nephrotoxins)
- worsening clinical status or toxicity
What are the steps to calculating adjusted doses?
- verify administration and sampling times – confirm levels are drawn at appropriate times in relation to doses, and doses are administered at appropriate times
- calculate ke
- calculate t1/2
- calculate actual peak (if drawn > 30 min post-infusion)
- calculate actual trough (if drawn > 30 min pre-dose)
- calculate Vd
- if measured trough is high, calculate time to achieve desired trough
- calculate new τ (dosing interval) – round to standard dosing intervals (ie. q4h, q6h, q8h, q12h, q18h, q24h, etc.)
- calculate new dose (K) – administered over 30 min
- estimate trough to be obtained with new k0 and τ
What are the assumptions for simplified dosing adjustments?
- serum drug concentrations are drawn at correct time and reflect steady-state
- drug follows first order, one compartment model PK
- therefore if dosing interval does not change, increase/decrease in dose will result in proportional increase/decrease in serum concentration
