Zhu Z Y, Li R C
Department of Pharmacy, Faculty of Medicine, Chinese University of Hong Kong, Shatin.
J Antimicrob Chemother. 1998 Jul;42(1):61-5. doi: 10.1093/jac/42.1.61.
The postantibiotic effect (PAE) exhibited by Pseudomonas aeruginosa after exposure to single doses of tobramycin was investigated under various pharmacokinetic conditions using an established in-vitro kinetic model. At equal doses of the antibiotic stimulating an intravenous bolus condition, the effects of varying elimination half-life on PAE were assessed. The PAE was longer when the rate of antibiotic elimination was lower. However, after correcting for the different degrees of antibiotic exposure using the area under the concentration-time curve above the MIC (AUC > MIC), a coherent PAE versus antibiotic exposure profile was obtained. The effects of increasing tobramycin dose and exposure time on PAE were investigated in another series of experiments; PAE was assessed during antibiotic exposure when the exponentially decreasing concentrations were above the MIC, at the MIC and below the MIC. A longer PAE was achieved at higher doses and changes were dependent on both the degree and time of exposure. For all the doses tested, the PAE was longest when the decreasing antibiotic concentrations were near or at the MIC. Shorter PAEs were detected at sub-MIC concentrations and diminished rapidly as antibiotic concentrations continued to decline. Such a decrease in PAE was counteracted by the longer exposure time, so that the total time for which the organism was under the influence of the antimicrobial effects, i.e. the sum of exposure time and PAE, remained steady at sub-MIC concentrations. Under these simulated pharmacokinetic conditions, present data support a substantial impact of pharmacokinetics on PAE. Along with MIC, AUC > MIC can be a useful pharmacokinetic parameter for PAE assessments. Should PAE be a relevant factor in antibiotic chemotherapy, both time and degree of antibiotic exposure would have to be considered.
使用已建立的体外动力学模型，在各种药代动力学条件下研究了铜绿假单胞菌单次暴露于妥布霉素后呈现的抗生素后效应（PAE）。在刺激静脉推注条件的等剂量抗生素下，评估了不同消除半衰期对PAE的影响。抗生素消除速率较低时，PAE较长。然而，使用高于最低抑菌浓度（AUC > MIC）的浓度-时间曲线下面积校正不同程度的抗生素暴露后，得到了一致的PAE与抗生素暴露曲线。在另一系列实验中研究了增加妥布霉素剂量和暴露时间对PAE的影响；在抗生素暴露期间，当指数下降的浓度高于MIC、处于MIC和低于MIC时评估PAE。较高剂量时可实现更长的PAE，且变化取决于暴露程度和时间。对于所有测试剂量，当抗生素浓度下降至接近或处于MIC时，PAE最长。在亚MIC浓度下检测到较短的PAE，且随着抗生素浓度持续下降而迅速减小。PAE的这种降低被较长的暴露时间抵消，因此在亚MIC浓度下，生物体受抗菌作用影响的总时间（即暴露时间与PAE之和）保持稳定。在这些模拟的药代动力学条件下，现有数据支持药代动力学对PAE有重大影响。与MIC一起，AUC > MIC可作为评估PAE的有用药代动力学参数。如果PAE是抗生素化疗中的一个相关因素，则必须同时考虑抗生素暴露的时间和程度。
