Concepts

Reference
S.L. Green et. al.: Effects of hypoxia and azotaemia on the pharmacokinetics of amikacin in neonatal foals. Equine Veterinary J. 24(6), 475-479, 1992.

Significance
Gram-negative septicemia in the newborn foal is a major cause of neonatal mortality. Aminoglycoside antibiotics are an excellent choice for treatment or prevention of gram negative sepsis. However, aminoglycoside pharmacokinetics are different in foals than in adult horses. Consequently, it is important to make appropriate dose and interval corrections in order to provide safe and effective therapy. Especially in foals, it is possible to produce aminoglycoside toxicity without producing bactericidal aminoglycoside therapy!

Exercise (A)

1) Pharmacokinetic variables on the spreadsheet for simulation #1 are preset for a typical adult horse given gentamicin, simulation #2 is preset for a typical foal given gentamicin. Review the parameters paying particular attention to the volume of distribution (Vz) and the total clearance (Clt).

2) Both simulations

• Set Upper to 10. This represents the target concentration for EFFECTIVE gentamicin plasma concentrations.
• Set Lower to 1.0. This represents the toxic concentration threshold for gentamicin.
• 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). The lower concentration is a target minimum and concentrations must fall below this value before subsequent doses are given.

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

4) Review the graph of the simulations.

Exercise (B)

1)Change the interval setting of simulation #2 (foal) to 8, then 12, then 24 or until the CALCULATED minimum plasma concentration (Cmin) falls to at least 1.0.

2) Gradually adjust the dose setting of simulation #2 (foal) until the maximum plasma concentration (Cmax) rises to at least the level of the adult.

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

4) Review the graph of the simulations.

Question (A)

1) What two effects (on plasma concentration) are produced by the change in the volume of distribution described for foals?

Questions (B)

2) What general recommendations can be made for the proper dose and interval of aminoglycosides given to neonatal foals?

3) Examine the plot of the plasma concentration profile for the foal after you make your final dose adjustment. The plasma concentrations are below MIC for typical sensitive organisms (2.0 - 3.0 µg/ml) for about 6 hours out of each dose interval. What could you do for this patient to provide continuous antimicrobial therapy without risking gentamicin intoxication? (It should be clear that changing doses and intervals of gentamicin will not work. You need to think outside the pharmacokinetic box.)