Posted by James
It is generally accepted that inhaled p-agonists are efficacious in the treatment of acute asthma in patients presenting to the emergency department. More controversial, however, is the choice of dose, frequency of treatment, and method of delivery associated with optimal bronchodilation. Currently, standard therapy in most hospitals involves the administration of a Э-agonist at frequent intervals, often every 30 to 120 minutes in acutely ill patients. However, this approach is labor intensive and requires repeated visits by the respiratory therapist. In addition, relatively high doses of medication are used in an intermittent fashion potentially resulting in peaks and troughs of bronchodilator delivery over time. One appealing alternative has been the administration of (3-agonist by continuous nebulization. The pharmacologic rationale for this approach is analogous to that used when systemic agents such as heparin or ami- nophylline are given via continuous infusion rather than the bolus technique. Read the rest of this entry »
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.
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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).
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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.
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Organism
The isolate of P aeruginosa used in this study to induce endocarditis has been described in detail elsewhere. The MBC of this strain as determined in cation-supplemented Mueller-Hinton broth for amikacin is 2ug/ml, while that for gentamicin and tobramycin is 1 ug/ml.
Endocarditis
The details of the catheterization and induction of aortic endocarditis in rabbits have been published previously. Briefly, a transcarotid catheter is passed across the aortic valve to induce sterile endocarditis on the leaflet. Pseudomonal endocarditis is produced 24 hours after catheterization by injecting about 10 cfu of saline-washed cells intravenously. Positive blood cultures for P aeruginosa 24 hours after inoculation serve as presumptive evidence of the induction of bacterial endocarditis. In the present study the model of endocarditis was used to assess densities of infected aortic vegetations.
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Posted by James
Therapeutic outcomes in humans with aortic valve endocarditis remain relatively poor, particularly with virulent valvular pathogens (eg, Staphylococcus aureus and Pseudomonas aeruginosa). Aminoglyco- side-based regimens have not had a major salutary impact on the outcomes of treatment of these latter endocarditides, despite in vitro susceptibilities of these bacterial strains to such agents. This subopti- mal efficacy of aminoglycosides in human endocarditis has suggested potential impairment in either intravegetation penetration or distribution of these agents within cardiac vegetations.
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Posted by James
Serum total LD was elevated in all three groups of patients and there was much overlapping between the three groups (Fig 4). This enzyme system was not capable of differentiating the groups from one another. These findings agree with our previous experimental results which suggest that LD may be only minimally elevated by acute bowel infarction but other conditions (such as myocardial infarctions or major aortic reconstruction) can cause elevations above the upper limits of normal for this enzyme.
The ratio of LD/LD/2 was quite capable of differentiating patients with AMI from patients with acute bowel infarctions and patients undergoing major AAS (Fig 5). The only patients who had LD,/LD2 ratios greater than 1.00 were those who had electrocardio- graphically proven AMI. None of the patients in the other two groups had this isoenzyme change in any of the serum samples evaluated. Other clinical conditions which can cause this change in LD/LD2 ratio are renal infarction and hemolysis of blood samples. These conditions can be differentiated from acute bowel infarction or myocardial infarction on a clinical basis.
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