Meropenem for treating KPC-producing Klebsiella pneumoniae bloodstream infections: Should we get to the PK/PD root of the paradox?
Meropenem for treating KPC-producing Klebsiella pneumoniae bloodstream infections: Should we get to the PK/PD root of the paradox?
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DOI：
10.1080/21505594.2016.1213476
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发表时间：
2017-01-01
期刊：
影响因子：
5.2
通讯作者：
Mattioli, Francesca
中科院分区：
文献类型：
--
作者：
Del Bono, Valerio;Giacobbe, Daniele Roberto;Mattioli, Francesca
本研究的目的是评估在MEM最低抑菌浓度（MIC）16 mg/L的情况下，美罗培南（MEM）在由产碳青霉烯酶肺炎克雷伯菌（KPC-Kp）引起的血流感染（BSI）危重患者中实现的药代动力学/药效学（PK/PD）目标。19例KPC-Kp BSI危重患者接受联合治疗，包括MEM、替加环素加粘菌素或庆大霉素（根据药敏试验）。MEM以每8小时输注2 g的方式延长3小时给药，或根据肾功能进行调整。通过高效液相色谱法测定MEM血浆浓度。MEM的PK/PD目标定义为T > 40% 1xMIC和T > 40% 4xMIC。基于MEM的血浆水平和其他药物的固定血浆浓度，通过时间杀灭试验评估MEM和联合给药药物之间可能的协同作用。在19例患者中，MEM均未达到任何PK/PD目标。1、3和15株分离株的实际MEM MIC分别为256、512和1024 mg/L。然而，理论上，对于MIC等于8、16、32和64 mg/L，分别有95%、68%、32%和0%的分离株可以实现T > 40% 1xMIC的PK/PD目标。MEM和联合给药药物之间未观察到协同作用。总之，由于KPC-Kp具有非常高的MEM MIC，因此高剂量MEM未能在19例BSI患者中达到PK/PD目标。在理论基础上，我们的结果表明MEM对MIC高达32 mg/L的耐药血液分离株可能有用。
The objective of this study was to assess the achievement of pharmacokinetic/pharmacodynamic (PK/PD) targets of meropenem (MEM) in critically-ill patients with bloodstream infections (BSI) due to Klebsiella pneumoniae-carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) with MEM minimum inhibitory concentrations (MICs) 16mg/L. Nineteen critically-ill patients with KPC-Kp BSI were given combination therapy including MEM, tigecycline, plus colistin or gentamicin (according to susceptibility testing). MEM was administered as an extended 3-hour infusion of 2g every 8hours, or adjusted according to renal function. MEM plasma concentrations were determined by high-performance liquid chromatography. PK/PD targets for MEM were defined as T > 40% 1xMIC and T > 40% 4xMIC. Possible synergisms between MEM and coadministered agents were assessed by time-kill assays based on plasma levels for MEM and on fixed plasma concentrations for the other agents. In none of 19 patients MEM reached any PK/PD target. The actual MEM MICs were 256, 512, and 1024mg/L in 1, 3, and 15 isolates, respectively. However, theoretically, the PK/PD target of T > 40% 1xMIC could have been achieved in 95%, 68%, 32% and 0% of the isolates for MIC equal to 8, 16, 32, and 64mg/L, respectively. No synergisms were observed between MEM and coadministered agents. In conclusion, high-dose MEM failed to reach PK/PD targets in 19 patients with BSI due to KPC-Kp with very high MEM MICs. On a theoretical basis, our results suggest a possible usefulness of MEM against resistant blood isolates with MICs up to 32mg/L.