Service d'Hématologie, AP-HP, Hôpital Cochin, Paris, France.
Equipe mobile d'infectiologie, AP-HP, Centre Université de Paris-Cochin, Paris, France.
J Antimicrob Chemother. 2020 Oct 1;75(10):2960-2968. doi: 10.1093/jac/dkaa275.
Optimal dosing of antibiotics is critical in immunocompromised patients suspected to have an infection. Data on pharmacokinetics (PK) of meropenem in patients with haematological malignancies are scarce.
To optimize dosing regimens, we aimed to develop a PK population model for meropenem in this population.
Patients aged ≥18 years, hospitalized in the haematology department of our 1500 bed university hospital for a malignant haematological disease and who had received at least one dose of meropenem were eligible. Meropenem was quantified by HPLC. PK were described using a non-linear mixed-effect model and external validation performed on a distinct database. Monte Carlo simulations estimated the PTA, depending on renal function, duration of infusion and MIC. Target for free trough concentration was set at >4× MIC.
Overall, 88 patients (181 samples) were included, 66 patients (75%) were in aplasia and median Modification of Diet in Renal Disease (MDRD) CLCR was 117 mL/min/1.73 m2 (range: 35-359). Initial meropenem dosing regimen ranged from 1 g q8h to 2 g q8h over 30 to 60 min. A one-compartment model with first-order elimination adequately described the data. Only MDRD CLCR was found to be significantly associated with CL. Only continuous infusion achieved a PTA of 100% whatever the MIC and MDRD CLCR. Short duration of infusion (<60 min) failed to reach an acceptable PTA, except for bacteria with MIC < 0.25 mg/L in patients with MDRD CLCR below 90 mL/min/1.73 m2.
In patients with malignant haematological diseases, meropenem should be administered at high dose (6 g/day) and on continuous infusion to reach acceptable trough concentrations.
在疑似感染的免疫功能低下患者中，抗生素的最佳剂量至关重要。有关血液恶性肿瘤患者中美罗培南药代动力学（PK）的数据很少。
为了优化给药方案，我们旨在为此人群开发美罗培南的 PK 群体模型。
年龄≥18 岁、因恶性血液病住院于我们 1500 张床位的大学附属医院血液科且至少接受过一次美罗培南治疗的患者符合条件。美罗培南通过 HPLC 定量。采用非线性混合效应模型描述 PK，并在独立数据库上进行外部验证。蒙特卡罗模拟根据肾功能、输注时间和 MIC 估计 PTA。游离谷浓度的目标设定为>4×MIC。
共有 88 名患者（181 份样本）入选，66 名患者（75%）处于再生障碍期，中位改良肾脏病膳食研究（MDRD）CLCR 为 117 mL/min/1.73 m2（范围：35-359）。初始美罗培南给药方案范围为 1 g q8h 至 2 g q8h，输注时间 30-60 分钟。一阶消除的单室模型很好地描述了数据。仅 MDRD CLCR 与 CL 显著相关。无论 MIC 和 MDRD CLCR 如何，只有连续输注才能达到 100%的 PTA。输注时间较短（<60 分钟）除了 MIC<0.25mg/L 的细菌和 MDRD CLCR<90mL/min/1.73m2 的患者外，无法达到可接受的 PTA。
在恶性血液病患者中，美罗培南应给予高剂量（6 g/天）并连续输注，以达到可接受的谷浓度。
