Concepts

Reference
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.

Significance
A new approach to aminoglycoside therapy is being advocated by some infectious disease specialists. Rather than giving amikacin at a dose rate of 10 mg/kg every 8 hours, they advocate single daily doses of 24 mg/kg. (The practice in general is referred to as pulse dosing. It relies on an improved kill rate of the bacteria by high concentrations of the antimicrobial, to offset long periods when drug concentrations fall below MIC.) 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.

Exercise

1) Pharmacokinetic variables on the spreadsheet are preset for a typical dog given amikacin.

2) Both simulations:

• Set Upper (in this situation the Effective concentration) to 20
• Set Lower (Toxic concentration) to 1.
• It may seem strange to put the toxic concentration below the effective concentration, but this is consistent with the way aminoglycosides produce their major toxicity (failure to allow concentrations to fall far enough). This is a target minimum, concentrations must fall below this value before subsequent doses are given.

• Set the dose to 10.0 mg/kg
• Set the weight to any reasonable dog weight
• Set the interval to 8

• Set the dose to 30 mg/kg
• Set the weight to any reasonable dog weight
• Set the interval to 24

3) Review the calculated values at the bottom of the worksheet.

4) Review the graph of the simulations.

Questions

1) Calculate the dose rate for each regimen. What was Cave for each dose regimen? (Equations provided in "Equations section" under program help).

2) Which regimen is more likely 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)Which dose regimen allows concentrations to fall below MIC for the greatest period of time?

4) For many drugs, the average plasma concentration (Cave) is a good indicator of efficacy or toxicity. Is Cave an adequate indicator of likely efficacy for amikacin ? Why or Why not? (see "Pulse dosing" in the introduction to this exercise)