Intravegetation antimicrobial distribution in aortic endocarditis analyzed by computer-generated model. Implications for treatment.

Abstract

The distribution of antibiotics into cardiac valvular tissues is incompletely understood. By integrative computer modeling, we have used previously obtained pharmacokinetic data in experimental endocarditis to characterize aminoglycoside distribution within various geographic sectors of aortic vegetations of rabbits and humans in the current study. In rabbits with pseudomonal aortic endocarditis receiving a standard regimen of amikacin (15 mg/kg every eight hours), sub-MBC levels of the drug for the infecting organism were calculated in the center of 0.38-cm vegetations; this occurred despite supra-MBC levels calculated in plasma and more peripheral loci of the vegetation. In contrast, with a high-dose regimen of amikacin (40 mg/kg every eight hours), supra-MBC drug levels were calculated throughout the entire vegetation for at least 50 percent of the dosing interval. Using similar computer-generated approaches, these data in the rabbit were approximately in simulated aminoglycoside penetration of 10-mm human aortic vegetations. Aminoglycoside regimens designed to yield supra-MBC serum levels in both normal and rapid drug eliminators consistently achieved sub-MBC levels in the center of the vegetation. Computer simulations also confirmed that daily doses of aminoglycoside at least two to four times higher than those ordinarily recommended are necessary to consistently achieve uniform supra-MBC intravegetation levels for an entire dosing interval. Such computer-generated data support the concept of maldistribution of aminoglycosides in aortic endocarditis and provide a rationale for investigating the use of high-dose regimens of aminoglycoside in treating experimental endocarditis.