Intravegetation Antimicrobial Distribution in Aortic Endocarditis Analyzed: MATERIALS AND METHODS part 2

Posted by James

Pharmacokinetic Studies

Rabbit Aortic Vegetations. In the present investigation, we used the previous results of serum amikacin pharmacokinetics in rabbits following a single intravenous bolus of either 15 or 40 mg/kg and fit them to a one-compartment model using weighted, nonlinear least-squares analysis, employing ADAPT (Drs. David D’Argenio and Alan Schumitzky, Laboratory of Applied Pharmacokinetics, University of Southern California, Los Angeles). The pharmacoki­netic parameters of volume of distribution and elimination rate constants were thus found. We examined a two-compartment model for this purpose and found no significant differences in pharmaco­kinetic and diffusion parameters, as compared to the one-compart­ment model; we chose the simpler one-compartment model for this study.

The average radius of a rabbit aortic vegetation in the present study was calculated using the formula, V = 4/3 nr, where V (volume) equals the average vegetation weight divided by vegetation density. Average weights of aortic vegetations were determined from previous data. We were able to approximate the average vegetation density by observing the flotation characteristics of vegetations in various solvents of known specific gravity. For this purpose, we induced experimental pseudomonal endocarditis as delineated previously in two rabbits. Forty-eight hours after induc­tion, the animals were killed and their hearts removed. Individual aortic vegetations were removed, washed in saline, and suspended in either water (SG = 1.0), 10 percent acetic acid (1.005), aniline dye (1.02), glycerin (1.04), or phenol (1.06), yielding a specific gravity of about 1.01.

The diffusion coefficient of amikacin into rabbit aortic vegetations was determined as follows: We first calculated drug concentrations at various radii within a volume equalling the average rabbit vegetation volume for a given diffusion coefficient (based on 0.38- cm diameter for vegetation weighing 0.028 g). We multiplied these concentrations with a weighing factor corresponding to the per­centage of surface area, so that each concentration would contribute a certain percentage to the overall drug concentration. A spline curve was fit to these data points, and this expression was integrated from the center to periphery of the vegetation. Using nonlinear least-squares regression, the diffusion coefficient was found which had the model-estimated average antibiotic concentrations which best fit the measured data obtained in our prior study.

Human Aortic Vegetations. For assessing penetration into human aortic vegetations, we assumed that the diffusion coefficient was the same as in the rabbits. This assumption appears reasonable, since the histopathologic features of vegetations in human and rabbit endocarditis are virtually identical. Since pseudomonal endocar­ditis in humans is a disease virtually limited to the intravenous drug-abusing population, we used the published aminoglycoside population pharmacokinetics of volume of distribution and serum half-life as found in hospitalized intravenous drug abusers. Then using this model, typical time courses of serum concentrations resulting from typical dosing regimens were generated. Also, to accurately assess intravegetation penetration of aminoglycoside in febrile drug addicts, we calculated such data during computer simulations in patients who were both “rapid” and “normal” eliminators of these agents.
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Using the diffusion coefficient determined from the rabbit model, we calculated the penetration of aminoglycosides into 1.0-cm aortic vegetations of humans from the near-center (eg, 0.1 r) to the periphery of the lesion (eg, 0.8 r), over the time course of serum concentrations during a typical dose interval. We also determined the following information: (1) given a specific daily dose of amino­glycoside to a human with an aortic vegetation of 1.0 cm, what dosing interval would need to be employed to achieve supra-MBC drug concentrations throughout the vegetation over the entire interval; and (2) given a specific daily dosing interval of the aminoglycoside, what dose of drug would have to be used to achieve supra-MBC levels throughout the vegetation over the entire dosing interval.