Intravegetation Antimicrobial Distribution in Aortic Endocarditis Analyzed: DISCUSSION

Posted by James

The current study used a computer-simulated model of endocarditis vegetation developed by Eng et al to estimate antibiotic levels in different geographic sec­tors of the aortic vegetation. Using this method, the penetration of certain aminoglycosides into infected aortic valve vegetations of both humans and rabbits was calculated. We modified their model by (1) using aminoglycoside pharmacokinetic parameters experi­mentally defined both in humans and in experimental endocarditis; (2) using diffusion coefficients deter­mined from experimental data for overall aminogly­coside penetration into infected aortic vegetations; and (3) using published data on protein binding of aminoglycosides to calculate free drug levels in serum and vegetation.

Several interesting observations were noted in the current study. In rabbits receiving “standard” dosing regimens of amikacin (15 mg/kg intravenously) sub- MBC drug levels were calculated to be present in the center of the vegetation throughout an eight-hour dosing interval; this occurred despite supra-MBC levels being achieved in plasma, as well as in the more peripheral parts of the vegetation. Increasing the dose of amikacin to 40 mg/kg in rabbits resulted in estimated drug levels exceeding the infecting pseudomonal strains MBC for at least 50 percent of the eight-hour dosing interval in the near center of the aortic vege­tation. Using the same diffusion model for humans with aortic vegetations 1.0 cm in diameter, it was clearly shown that aminoglycoside dosing regimens designed to yield targeted peak serum drug levels within the generally acceptable range are inadequate to achieve supra-MBC concentrations at the vegeta­tions near center; this was particularly so in patients who are rapid eliminators of aminoglycosides such as febrile drug addicts, a prime target population for endocarditis. Lastly, computer simulations showed that daily doses of aminoglycoside at least twice those recommended to achieve adequate plasma levels for the majority of severe aerobic gram-negative bacillary infections are required to achieve supra-MBC levels throughout the aortic vegetation for an entire eight- hour dosing interval. These data are compelling in light of the recent clinical data that the ratio between peak plasma aminoglycoside concentrations (or per­haps AUCs), on one hand, and MICs or MBCs, on the other hand, are important determinants of outcome with aminoglycoside therapy.

Our results showing the improvement in calculated aminoglycoside penetration into aortic vegetations following high-dose regimens may partially explain the observations of Reyes and associates; these in­vestigators found that patients given high-dose ami­noglycoside regimens (eg, gentamicin at 8 mg/kg/day) for left-sided pseudomonal endocarditis had superior outcomes to those receiving “standard-dose” regi­mens. Also, Kapusnik et al have shown that single, large daily doses of tobramycin (30 mg/kg) were more effective than equivalent total daily doses given at four-hourly intervals in nonneutropenic guinea pigs with experimental pseudomonal pneumonitis. This was related to the inability of the low-dose short- interval regimen to prevent bacterial regrowth during the latter part of the dosing interval. In contrast, the superior efficacy of the high-dose, long-interval ami­noglycoside regimen was related to a combination of enhanced concentration-dependent killing, in vitro postantibiotic growth suppression and leukocyte en­hancement effects. This observation was confirmed in the neutropenic guinea pig model of pseudomonal pneumonia in which the single, large daily-dose regi­men of aminoglycoside were no longer superior to the low-dose, short-interval regimen, presumably through the loss of the in vivo postantibiotic leukocyte enhance­ment phenomenon in the neutropenic host. The addition of mezlocillin to tobramycin in this latter neutropenic model was able to prevent bacterial regrowth in the lungs. These data lend support to our findings in the current study that higher dosing regimens of aminoglycosides may enhance the efficacy of treatment of selected pseudomonal infections, par­ticularly those occurring in areas of relatively poor drug penetration, such as the center of cardiac vege­tations. It is clear that the postantibiotic effect is an important correlate of therapeutic outcome in experi­mental endocarditis; however, it should be empha­sized that since aortic vegetations are relatively devoid of leukocytes, even high-dose aminoglycoside dosing strategies may need to be combined with (3-lactam drugs to prevent bacterial regrowth in the latter parts of long dosing intervals.
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The other aspect of higher-dose or shorter-interval treatments (or both) with aminoglycoside in endocarditis is possible enhancement of toxicity. Wood et al have recently shown that given the same high daily dose of tobramycin in rats (60 mg/kg), renal injury occurred more commonly in animals receiving more- frequent dosing regimens, despite equivalent effica­cies of both longer and shorter dosing intervals in a model of subcutaneous abscess. These data agree with our findings in the computer simulations of aminogly­coside penetration of aortic vegetations; we found that the more-frequent dosing regimens necessary to achieve supra-MBC aminoglycoside levels throughout the dosing interval at the vegetations center resulted in steady-state trough serum levels consistently in excess of those associated with renal toxicity and ototoxicity in man (>2 ug/ml¹²).

The current study implicates altered diffusion char­acteristics of aminoglycosides within aortic vegeta­tions, although additional mechanisms such as hydro­phobic, electrostatic, or covalent bonding may play a role in the maldistribution of these agents in endocar­ditis. The adaptation of our computer simulations to the therapy of patients with aortic endocarditis must await rigorous testing of this approach in the animal model. We are currently examining the relative effi­cacies of aminoglycoside regimens in experimental aortic pseudomonal endocarditis administered at the dosage and interval regimens calculated by our com­puter simulations to achieve supra-MBC levels throughout the cardiac vegetation.