Tegeder I, Bremer F, Oelkers R, Schobel H, Schüttler J, Brune K, Geisslinger G
Department of Experimental and Clinical Pharmacology and Toxicology, University Erlangen/Nürnberg, Erlangen, Germany.
Antimicrob Agents Chemother. 1997 Dec;41(12):2640-5. doi: 10.1128/AAC.41.12.2640.
The pharmacokinetics of imipenem-cilastatin were investigated in 12 critically ill patients with acute renal failure (ARF) managed by continuous veno-venous hemofiltration (CVVH) while receiving a fixed combination of 500 mg of imipenem-cilastatin intravenously three or four times daily. No adverse drug reactions were observed. Plasma and hemofiltrate samples were taken at specified times during one dosing interval, and the concentrations of imipenem and cilastatin were determined by high-performance liquid chromatography. Pharmacokinetic variables were calculated by a first-order, two-compartment pharmacokinetic model for both substances. Total clearances of imipenem and cilastatin (mean +/- standard deviations) were 122.2 +/- 28.6 and 29.2 +/- 13.7 ml/min, respectively, with hemofiltration clearances of 22.9 +/- 2.5 and 16.1 +/- 3.1 ml/min, respectively, and nonrenal, nonhemofiltration clearances of 90.8 +/- 26.3 and 13.2 +/- 13.9 ml/min, respectively. Mean imipenem dosage requirements were approximately 2,000 mg/24 h (2,111.8 +/- 493.4 mg/24 h). They were calculated in order to achieve an average steady-state concentration of 12 mg/liter to ensure that concentrations in plasma exceeded the MICs at which 90% of intermediately resistent bacteria are inhibited (8 mg/liter) during the majority of the dosing interval. By contrast, the recommended dosage for patients with end-stage renal failure (ESRF) and infections caused by intermediately resistant bacteria is 1,000 mg/24 h. This remarkable difference may be due (i) to differences in the nonrenal clearance of imipenem between patients with ARF and ESRF and (ii) to the additional clearance by the hemofilter. Since the total clearance of cilastatin was low, marked accumulation occurred, and this was particularly pronounced in patients with additional liver dysfunction. Thus, in patients with ARF managed by CVVH, rather high imipenem doses are required, and these inevitably result in a marked accumulation of cilastatin. The doses of imipenem recommended for patients with ESRF, however, will lead to underdosing and inadequate antibiotic therapy.
对12例接受连续性静脉-静脉血液滤过（CVVH）治疗的急性肾衰竭（ARF）危重症患者进行了亚胺培南-西司他丁的药代动力学研究，这些患者每日静脉注射3或4次固定剂量组合（500mg）的亚胺培南-西司他丁。未观察到药物不良反应。在一个给药间隔内的特定时间采集血浆和血液滤过液样本，采用高效液相色谱法测定亚胺培南和西司他丁的浓度。两种物质的药代动力学变量均通过一级二室药代动力学模型计算。亚胺培南和西司他丁的总清除率（平均值±标准差）分别为122.2±28.6和29.2±13.7ml/min，血液滤过清除率分别为22.9±2.5和16.1±3.1ml/min，非肾、非血液滤过清除率分别为90.8±26.3和13.2±13.9ml/min。亚胺培南的平均剂量需求约为2000mg/24h（2111.8±493.4mg/24h）。计算这些剂量是为了达到12mg/L的平均稳态浓度，以确保在大多数给药间隔期间血浆浓度超过能抑制90%中度耐药菌的最低抑菌浓度（8mg/L）。相比之下，终末期肾衰竭（ESRF）且由中度耐药菌引起感染的患者推荐剂量为1000mg/24h。这种显著差异可能是由于：（i）ARF患者和ESRF患者亚胺培南非肾清除率不同；（ii）血液滤过器的额外清除作用。由于西司他丁的总清除率较低，出现了明显蓄积，在合并肝功能不全的患者中尤为明显。因此，对于接受CVVH治疗的ARF患者，需要较高剂量的亚胺培南，而这不可避免地导致西司他丁明显蓄积。然而，推荐给ESRF患者的亚胺培南剂量会导致给药不足及抗生素治疗不充分。
