Module 6. Clinical implications of various dosing protocols on amikacin safety and efficacy.

Objectives

Having completed this exercise and based on pharmacokinetic constants and data, students should be able to:

Significance

R.D. Moore et al: Clinical response to aminoglycoside therapy: Importance of the ratio of peak concentration to minimal inhibitory concentration. J. Infectious Diseases 155(1), 93-99, 1987.

J.D. Baggott et al: Clinical pharmacokinetics of amikacin in dogs. American J of Veterinary Research 46(8), 1793 - 1796, 1985.

Dosage recommendations for amikacin range from 10 mg/kg every 8 hours to 30 mg/kg every 24 hours. At this time, there seems to be a clinician preference for high doses once each day (so-called pulse dosing). The approach is thought to be as efficacious and less toxic (nephrotoxicity is associated with high trough concentrations rather than high peak concentrations). MIC values for susceptible organisms range from 2 to 8 μg/ml. It requires 2 - 3 x MIC to reach minimum bactericidal concentrations (MBC). Some authors refer to Cmax: AUC ratios as these may explain the efficacy of pulse dosing.

Exercise

Download amikacindosage.xlsx, the worksheet for this module. Depending on your settings, you may have to "enable editing" in order to make the changes suggested by the exercise.

The pharmacokinetic variables on the spreadsheet are preset for a typical dog given amikacin. Simulation #1 is set for a dose interval of 8 hours (and the appropriate dose) and simulation #2 is set for a dose interval of 24 hours.

Target concentrations

Manipulate pharmacokinetic parameters

Inspect

Calculated values

Steady-State Concentrations (for repeated doses during therapy).

Graphs

Assess

Questions (Key)

  1. The Cave value is the same for both simulations and at all clearance settings. Why is this so?
  2. Which regimen is more certain to produce bactericidal concentrations? Remember, you are unlikely to KNOW the MBC for a particular bacterial infection. You are interested in improving the ODDS that the bacteria is exposed to sufficiently high concentrations.
  3. If you do not know the patient's renal status, which regimen is less likely to result in toxicity?
  4. Which regimen is more likely allows the plasma concentrations to fall so low that the bacteria start to regrow at the end of each dose interval?