Intravegetation Antimicrobial Distribution in Aortic Endocarditis Analyzed: RESULTS

Posted by James

Penetration of Aminoglycoside into Rabbit Aortic Vegetations

Using experimentally determined data on the half- lives and peak serum concentrations of amikacin found in the previous rabbit model of aortic endocarditis following a single initial intravenous bolus of either 15 or 40 mg/kg,⁴ a diffusion coefficient of 0.7 X 10^-6 cm² s¹ was defined. The coefficient of variation was 11.3 percent for the 15-mg/kg dose (r = 0.905; p<0.01) and was 21 percent for the 40-mg/kg dose (r = 0.968; p<0.01).

Because of the small average diameter of rabbit vegetations (—0.38 cm), greater than 90 percent of the simulated steady-state peak and trough levels of ami­kacin were achieved with the first of the repetitive eight hourly intravenous doses of either 15 or 40 rng/ kg amikacin. Figure 1 represents the computer-simu­lated variations in free amikacin concentrations during a typical dosing interval in a spherical aortic vegetation of 0.38 cm over an eight-hour dosing interval following an intravenous dose of either a 15 or 40 mg/kg. The data characterize time-concentration profiles for ami­kacin at three different intravegetation sectors (periph­ery, 0.5 r, and near center) and compare these values to the infecting pseudomonal organisms MBC for this agent (2jig/ml). As noted, following the 15 mg/kg dosing regimen, supra-MBC antibiotic levels are achieved only at the vegetations periphery (0.8 r) and at 0.5 r, while substantially sub-MBC drug levels are observed at the near center (0.1 r) of the vegetation. In contrast, following the higher dosing regimen of amikacin (40 mg/kg), supra-MBC drug levels were achieved throughout the entire vegetation. Moreover, when evaluating the time-concentration curves of amikacin at the vegetations center following the higher dosing regimen, this dosing strategy achieved supra- MBC drug levels at the vegetations center for more than 50 percent of the eight-hour dosing interval (data not shown).

Penetration of Aminoglycoside into Human Aortic Vegetations

Table 1 delineates the calculated aminoglycoside daily dosing regimen necessary to achieve therapeu­tically acceptable steady-state peak serum drug levels in either normal or rapid eliminators of aminoglyco­sides. These generally accepted peak levels for the treatment of severe aerobic Gram-negative bacillary infections such as pneumonia or endocarditis are given as 6ug/ml to lOixg/ml for gentamicin or tobramycin and 20 ug/ml to 30ug/ml for amikacin. Table 1 shows the calculated peak and trough intravegetation levels of aminoglycoside which would be achieved at various sectors of the vegetation, given such daily dosing drug regimens. Using the experimentally de­fined MBC for the infecting pseudomonal strain of 2 ug/ml for amikacin and lug/ml for gentamicin and tobramycin, it is clear that the peak and trough drug levels at the vegetations center never equal or exceed the organisms MBC following such “standard” dosing regimens. These data also demonstrate the phenome­non of “dampening”; ie, closer to the center of the vegetation yields lower peak and higher trough drug levels, while nearer to the periphery of the vegetation, peak levels tend to be higher and trough levels lower than observed at the vegetations center (Fig 2).
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Table 1—Projected Target Doses of Aminoglycosides in Humans to Achieve Therapeutically Acceptable Target Plasma Levels Relationship with Peripheral and Central Intravegetation Levels

		Peak/Trough Levels, ug/ml
	Target
Drug and Group	Dose,		Periphery	Center
of Patients	mg/kg/day*	Plasma	(0.8 r)	(0.1 r)
Gentamicin or
tobramycin
Rapid elim­	8.2	6.0/0.45	2.7/1.3	0.27/0.26
inators
Normal elim­	4.5	6.0/1.4	3.1/2.1	0.34/0.33
inators
Amikacin
Rapid elim­	29.4	21.6/1.62	9.8/4.75	0.98/0.92
inators
Normal elim­	15.2	20.2/4.6	10.5/7.1	1.16/1.11
inators

Computer simulations were then run to ascertain the aminoglycoside daily dosing regimens required in both “rapid” and “normal” drug eliminators to achieve supra-MBC levels throughout the vegetation for an entire dosing interval of eight hours. As noted in Table 2, the daily dose for each of the aminoglycosides would have to be about 2 to 4 times higher than the “standard” regimens (Table 1) in order to achieve the desired goal of uniform supra-MBC intravegetation levels for the entire dosing interval.

FIGURE 1. Computer-simulated variations in free amikacin concen-trations in rabbit spherical aortic vegetation of 0.38 cm over eight- hour dosing interval in peripheral vs central sectors of vegetation. A (top), 15 mg/kg intravenous dosing regimen; and В (bottom), 40 mg/kg.

Computer simulations were also run to determine what effect a shortening of the dosing interval from eight to four hours would have on the intravegetation aminoglycoside levels following standard dosing regi­mens (as outlined in Table 1). By shortening the dosing interval, the same mean concentrations of drug were achieved in the vegetations center, as observed with the eight-hour dosing interval; however, the peak and trough concentrations were significantly dampened in relation to the eight-hour dosing interval. It should be emphasized that shortening the dosing interval to four hours in this model simulation resulted in higher trough serum levels of aminoglycosides than with the eight-hour dosing interval. Such trough levels were often in the range associated with renal toxicity or ototoxicity (or both) in the human (>2 ug/ml to 4 ug/ ml).
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Table 2—Computer-Generated Ideal Target Aminoglycoside Doses To Achieve MBC-Equivalent Drug Levels throughout Aortic Vegetation

		Peak/Trough Levels, ng/ml
	Target			———- »
Drug and Croup	Dose,		Periphery	Center
of Patients	mg/kg/day*	Plasma	(0.8 r)	(0.1 r)
Gentamicin or
tobramycin
Rapid elim­	32.2	23.7/1.8	11.3/5.5	1.08/1.0
inators
Normal elim­	13.7	16.9/3.9	9.5/6.38	1.04/1.0
inators
Amikacin
Rapid elim­	64	47.2/3.5	21.4/10.4	2.14/2.0
inators
Normal elim­	27.3	36.2/8.3	18.9/12.8	2.08/2.0
inators

Computer simulations were also performed in which a continuous infusion, designed to maintain serum levels of gentamicin or tobramycin at 6 ug/ml, was employed. This resulted in sub-MBC levels being achieved at the center of human aortic vegetations (0.6 ug/ml; data not shown).

FIGURE 2. Computer-simulated amikacin time-concen-tration curves in spherical human vegetation (1.0 cm) at various geographic sectors, following administration of standard dose of amikacin (AMK) (15 mg/kg). A (top), Rapid drug eliminator; and В (bottom), Normal drug eliminator.