Pharmacokinetic dosing of aminoglycosides aims to achieve high peak concentrations for efficacy while minimizing toxicity. The volume of distribution and half-life determine dosing frequency, with the goal of peaks above minimum inhibitory concentrations and troughs below toxic levels. Dosing is calculated using equations relating the dose, volume of distribution, elimination rate constant, and desired concentration changes over time.

1. Aminoglycoside Dosing:
Pharmacokinetic Model
Rationale
Yazan Kherallah

2. Objectives
• Understand the rationale supporting the
pharmacokinetic dosing model
• Discuss and interpret pharmacokinetic
concepts that affect aminoglycoside dosing
– Volume of distribution
– Half-life / Elimination rate
• Utilize pharmacokinetics to properly dose
aminoglycosides

3. Pharmacokinetics (PK) vs.
Pharmacodynamics (PD)
• Definitions:
– PK: The process by which a drug is absorbed,
distributed, metabolized, and eliminated by the
body
– PD: The study of the action or effects of drugs on
living organisms
• In other terms:
– PK: what the body does to the drug
– PD: how the drug acts on the body
• One must understand the PD of a drug before
using PK to design a dosing regimen

4. Aminoglycoside PD
- Bactericidal
- Bind to 50S subunit to
inhibit DNA synthesis
Concentration dependent killing

5. Literature Support
• Multiple studies have demonstrated the
relationship of PK/PD for aminoglycosides
– Plasma levels and outcome
• Sepsis
• Pneumonia
– Peak:MIC ratio
– Altered Vd in the critically ill
• Goals
– Provide efficacious dosing
– Minimize drug toxicity

6. Association of Serum Levels and
Outcome
• Initial doses of 2 mg/kg gentamicin or
tobramycin (8 mg/kg amikacin) given to septic
patients (n=89)
– In combination with a β-lactam
• Therapeutic initial peaks
– Gent/tobra: > 5 mcg/ml
– Amikacin: > 20 mcg/ml
• Outcome = Mortality
– Therapeutic: 2.4% (1/41)
– Subtherapeutic: 20.9% (9/43)
J Infect Dis 1984;149(3):443-8

7. Association of Serum Levels and
Outcome
• Initial doses of 2 mg/kg gentamicin or tobramycin (8
mg/kg amikacin) given to pneumonia patients (n=37)
– In combination with a β-lactam
• Therapeutic initial peaks
– Gent/tobra: > 7 mcg/ml
– Amikacin: > 28 mcg/ml
• Outcome = “Successful Outcomes”
– Therapeutic: 78% (14/18)
– Subtherapeutic: 32% (6/19)
• Multivariate analysis
– Most important predictor of positive outcome
Am J Med 1984;77:657-662

8. Importance of Peak:MIC Ratio
• Initial doses of 2 mg/kg gentamicin or
tobramycin (8 mg/kg amikacin) given to sepsis
patients (n=236)
– In combination with a β-lactam
• 188/236 patients had favorable response to
antibiotics
• Most important factors for favorable response
(univariate analysis)
– Favorable underlying prognosis (p=0.0001; R=0.36)
– Maximal peak:MIC ratio > 10 (p=0.0005; R=0.21)
J Infect Dis 1987;155(1):93-9

9. Importance of Peak:MIC Ratio
Table of Peak:MIC ratios and relative odds of
favorable response
Max Peak:MIC
(mcg/ml)
Relative Odds 95% Confidence
Interval
< 2 1.00
2-<4 1.63 0.84-3.16
4-<6 1.83 1.09-3.03
6-<8 4.35 2.53-7.46
8-<10 6.49 3.56-11.82
>10 8.41 4.62-15.33
J Infect Dis 1987;155(1):93-9

10. Achieving Acceptable Peak:MIC
Ratios in the Critically Ill
• 53 SICU patients in septic shock given
gent/tobra
– Loading dose: 3 mg/kg of IBW or adjusted BW
• 50% of the difference between IBW and actual weight
• Mean initial peak = 8.1 + 0.3 mcg/ml
– Only achieved in 50% of patients
– Mean Vd = 0.29 L/kg (0.2-0.54 L/kg)
– 34% had increased Vd
• 4mg/kg dose is back-calculated
Surgery 1998;124:73-78

11. Serum Level Targets
Infection
Type
Goal
Gent/Tobra
Peak
Goal
Gent/Tobra
Trough
Goal
Amikacin
Peak
Goal
Amikacin
Trough
Pneumonia
/ Sepsis
8-10 mcg/ml < 2 mcg/ml 32-40
mcg/ml
< 8 mcg/ml

12. Aminoglycoside Elimination
12
10
8
6
2
Beta Phase
Gamma
Phase
Alpha
Phase

13. Dosing Modalities
Traditional Once-daily PK (SICU)
Dose 2mg/kg q8h 5-7mg/kg qday 4mg/kg once
Description Low peaks,
high troughs
High peaks, low
troughs
Therapeutic
peaks / troughs
Use in … Floor patients
(if at all)
Floor patients,
stable Vd, CrCL
ICU patients
Advantages None? High Peak:MIC
PAE
Low toxicity
High Peak:MIC
PAE
Low toxicity

14. Sample Once-daily Nomogram
Nicolau DP et al. Antimicrob Agents Chemother
1995;39(3):650-55.

15. Aminoglycoside Dosing Regimen
• Usually based on actual body weight (ABW)
• Administer:
– Gent/Tobra 4 mg/kg IV x 1
– Amikacin 16 mg/kg IV x 1
• Draw 1 hour post-infusion peak and 8-12
hour random level
• Goal peaks
– Gent/Tobra = 8-10 mcg/ml
– Amikacin = 32-40 mcg/ml

16. Pharmacokinetic Equations
• Calculate Vd
– Needed for dose adjustment
– Vd = Dose given (mg) / peak (mg/L)
• Calculate ke and t1/2
– Determine frequency of drug administration
– ke = ln (peak/random) / Δt
– t1/2 = 0.693 / ke
• In how many half lives should you re-dose?
• Predict when appropriate to re-dose
– Ct = Co e (-ke x t)

17. Case: Volume of Distribution
• JK is a 75 yo male is POD 2 ex lap for SBO
and is now septic and hypotensive
• Discussion on rounds leads to the initiation of
antibiotics
– Pip/Tazo 3.375 g IV q6h
– Vancomycin 1 g IV q12h
– Gentamicin….

18. Case: Volume of Distribution
• Patients weight:
– Actual = 85 kg
– IBW = 76 kg
• What dose do you want to give of
gentamicin?
• When do you draw levels to calculate
regimen?
Gentamicin 340 mg IV x 1 over 30 minutes
Draw levels 1 hour and 8 hours post infusion

19. Case: Volume of Distribution
• Gentamicin is ordered and given at 0900
(after speedy pharmacy processing!)
• Levels to follow
– 1030: 11.2 mcg/mL
– 1800: 6.7 mcg/mL
• Calculate Vd
• Normal Vd is:
Vd = 340 mg / 11.2 mg/L = 30.3 L
= 0.36 L/kg
0.25-0.3 L/kg

20. Case: Elimination and Half-life
• JK’s levels
– 1030: 11.2 mcg/mL
– 1800: 6.7 mcg/mL
• Calculate ke
• Calculate T1/2
ke = ln (1 hr level/8 hr level) / change in time
ln (11.2 / 6.7 ) / 7.5
0.0685 hrs-1
t1/2 = 0.693 / ke
≈ 10 hrs

21. Case: When to re-dose?
• If clearance remains stable, it can be
assumed that the next dose could be given in
4 half lives
• Ct = Co e (-ke x t) can be used to predict when a
level will be < 2 mcg/ml
– Re-arrange equation to
– This will give you how many hours until serum
concentration is < 2 mcg/ml
– JK:
t = [ln Co – 0.693] / ke
≈ 18 hours must elapse until level is
< 2 mcg/ml

22. Case: The Next Dose
• Utilizing the patient-specific Vd for JK, what is the
next dose of gentamicin?
• Things to consider…
– Changing Vd
• Active diuresis?
• Third spacing?
– Changing ke
• CVVHD
– Clotting? Increasing flow rates?
• Declining/improving renal function?
Dose = Vd x desired increase in serum level
= 30.3 L x 8 mg/L (why 8 mg/L?)
= 240 mg

23. Take Home Points
• Aminoglycosides should be administered with
the goal of achieving therapeutic peaks early
• Dose is related to Vd
– As volume increases, so does the dose (and the
reverse is true)
– Dose is independent of elimination
• Frequency of dose is related to half-life and
elimination

24. Equations to Know
• Dose is 4 mg/kg of actual or adjusted weight
• Volume of distribution:
– Vd = Dose given (mg) / peak (mg/L)
• Elimination constant (ke)
– ke = ln (peak/random) / Δt
• Half-life
– t1/2 = 0.693 / ke
• Time until level is safe for redosing:
– t = [ln Co – 0.693] / ke (for gent/tobra)
– t = [ln Co – 2.01] / ke (for amikacin)