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Antibiotic dosing recommendations are usually based on plasma or cerebral spinal fluid pharmacokinetic (PK) studies. However, as infections mainly occur in extracellular tissue fluid (ECF), corresponding unbound ECF antibiotic concentrations are responsible for the antimicrobial effect. Because of the blood-brain barrier, the cerebral antibiotic distribution is thought to be reduced compared with tissues without any physiological barrier. This study aims to determine meropenem (MPM) unbound concentrations in the brain and compare them with MPM concentrations in plasma to explore cerebral distribution of MPM in patients with acute brain injury.
After local ethic approval and written informed consent, two brain-injured patients, sedated, mechanically ventilated, receiving MPM for an infection and monitored by cerebral microdialysis (CMA 71, membrane length 10 mm, membrane diameter 0.6 mm, molecular cut-off 100 kDa; CMA, Stockholm, Sweden) were enrolled. The PK study succeeded to 1 g meropenem over 30 minutes and brain dialysates and blood samples were collected over 420 minutes. Probe recoveries were evaluated individually by retrodialysis. MPM was assayed by HPLC coupled with tandem mass spectrometry (LC-MS/MS).
For each of the two patients, the MPM brain AUC is much lower than plasma AUC and accordingly brain to serum AUC ratios are respectively 0.73 for Patient 1 (P1) and 0.14 for Patient 2 (P2). MPM concentration versus time curves in brain are delayed (time-to-peak in P1 = 100 minutes, in P2 = 80 minutes) and present a smooth peak compared with the corresponding curves in plasma (Figure (Figure1).1). Mean probe recoveries are respectively 19 ± 7% for P1 and 29 ± 7% for P2.
The MPM brain AUC is much lower than plasma AUC for the two patients enrolled, consistent with the PK theory in the presence of tissue with efflux transporters. More patients are needed to better understand MPM brain distribution characteristics.