[危重症患者每日一次氨基糖苷类药物治疗的血清水平调整剂量：一项前瞻性研究的结果]

Reimann I R, Meier-Hellmann A, Pfeifer R, Traut T, Schilling A, Stein G, Reinhart K, Hoffmann A

Institut für Klinische Pharmakologie, Friedrich-Schiller-Universität, Jena.

Anasthesiol Intensivmed Notfallmed Schmerzther. 1999 May;34(5):288-95. doi: 10.1055/s-1999-186.

OBJECTIVE

In critically ill patients, the adjustment of target peak and trough levels of tobramycin was investigated because aminoglycoside pharmacokinetics can be changed by multiple influences. Sufficient but not too high peak serum concentrations and low trough levels, however, should be achieved to ensure a therapeutic effect and to minimize toxicity.

METHODS

70 critically ill patients of 51 +/- 18 years were monitored daily during their aminoglycoside treatment on the intensive care unit targeting a peak of about 12 micrograms/ml 30 minutes after infusion and a trough level below 1 to 2 micrograms/ml. Dose recommendations were given daily, taking into consideration serum levels, dose predictions (Bayesian method, ABBOTTBASE), creatinine clearance and clinical findings. Creatinine clearance was estimated according to the Cockcroft-Gault-formula as well as directly by the urine collection method.

RESULTS

The standardized initial dose of 400 mg tobramycin led to average peak serum levels of 14.2 +/- 3.9 micrograms/ml in the patients with an apparent distribution volume of 0.345 +/- 0.074 L/kg. In 95% of the patients, the initial peak was higher than 8.5 micrograms/ml; levels higher than 20 micrograms/ml were observed in 7%, extremely low concentrations (below 5 micrograms/ml) in 2%. With individually adjusted doses between 160 and 560 mg, a mean peak of 11.5 +/- 2.7 micrograms/ml was measured subsequently. The levels amounted to 96 +/- 23% of the predicted values, deviations greater than 50% occurred in 5%. The target trough level was achieved in 99%, in less than 3% the dosing interval was extended up to 72 hours. A tobramycin clearance below 80 ml/min/1.73 m2 was associated with average 80% and 33% higher creatinine clearance values according to the Cockcroft-method and the direct method, respectively.

CONCLUSION

Target peak and trough aminoglycoside levels are adjustable even in critically ill patients. Reduced tobramycin clearance can be associated with normal creatinine clearance. Assuming an exact methodology, a reduced "direct" creatinine clearance, however, indicates a reduced drug clearance.

目的

在重症患者中，研究妥布霉素目标峰浓度和谷浓度的调整情况，因为氨基糖苷类药物的药代动力学可能受到多种因素影响而发生变化。然而，应达到足够但不过高的血清峰浓度以及较低的谷浓度，以确保治疗效果并将毒性降至最低。

方法

对70例年龄在51±18岁的重症患者在重症监护病房接受氨基糖苷类治疗期间进行每日监测，目标是输注后30分钟时峰浓度约为12微克/毫升，谷浓度低于1至2微克/毫升。每天根据血清水平、剂量预测（贝叶斯方法，ABBOTTBASE）、肌酐清除率和临床检查结果给出剂量建议。肌酐清除率根据Cockcroft - Gault公式以及直接通过尿液收集方法进行估算。

结果

400毫克妥布霉素的标准化初始剂量使表观分布容积为0.345±0.074升/千克的患者血清平均峰浓度达到14.2±3.9微克/毫升。95%的患者初始峰浓度高于8.5微克/毫升；7%的患者峰浓度高于20微克/毫升，2%的患者浓度极低（低于5微克/毫升）。随后，通过160至560毫克的个体化调整剂量，测得平均峰浓度为11.5±2.7微克/毫升。实际浓度为预测值的96±23%，5%的患者偏差大于50%。99%的患者达到了目标谷浓度，不到3%的患者给药间隔延长至72小时。根据Cockcroft方法和直接法，妥布霉素清除率低于80毫升/分钟/1.73平方米分别与肌酐清除率平均高80%和33%相关。