A meropenem pharmacokinetics model in patients with haematological malignancies

Background: 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. Objectives: To optimize dosing regimens, we aimed to develop a PK population model for meropenem in this population. Methods: Patients aged >= 18years, 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 >4x MIC. Results: Overall, 88 patients (181 samples) were included, 66 patients (75%) were in aplasia and median Modification of Diet in Renal Disease (MDRD) CLCR was 117mL/min/1.73m(2) (range: 35-359). Initial meropenem dosing regimen ranged from 1g q8h to 2g q8h over 30 to 60min. 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 (<60min) failed to reach an acceptable PTA, except for bacteria with MIC<0.25mg/L in patients with MDRD CLCR below 90mL/min/1.73m(2). Conclusions: In patients with malignant haematological diseases, meropenem should be administered at high dose (6g/day) and on continuous infusion to reach acceptable trough concentrations.