Meropenem concentrations in brain tissue of neurointensive care patients exceed CSF levels

Background: Inadequate antibiotic exposure in cerebral infections might have detrimental effects on clinical outcome. Commonly, antibiotic concentrations within the CSF were used to estimate cerebral target levels. However, the actual pharmacological active unbound drug concentration beyond the blood-brain barrier is unknown. Objectives: To compare meropenem concentrations in blood, CSF and cerebral microdialysate of neurointensive care patients. Patients and methods: In 12 patients suffering subarachnoid haemorrhage, 2000 mg of meropenem was administered every 8 h due to an extracerebral infection. Meropenem concentrations were determined in blood, CSF and cerebral microdialysate at steady state (n=11) and following single-dose administration (n=5). Results: At steady state, the free AUC(0-8) was 233.242.7 mg.h/L in plasma, 7.8 +/- 1.9 mg.h/L in CSF and 26.6 +/- 14.0 mg.h/L in brain tissue. The brain tissue penetration ratio (AUC(brain)/AUC(plasma)) was 0.11 +/- 0.06, which was more than 3 times higher than in CSF (0.03 +/- 0.01), resulting in an AUC(CSF)/AUC(brain) ratio of 0.41 +/- 0.16 at steady state. After single-dose administration similar proportions were achieved (AUC(brain)/AUC(plasma)=0.09 +/- 0.08; AUC(CSF)/AUC(plasma)=0.02 +/- 0.00). Brain tissue concentrations correlated well with CSF concentrations (R=0.74, P<0.001), but only moderately with plasma concentrations (R=0.51, P<0.001). Bactericidal thresholds were achieved in both plasma and brain tissue for MIC values <= 16 mg/L. In CSF, bactericidal effects were only reached for MIC values <= 1 mg/L. Conclusions: Meropenem achieves sufficient bactericidal concentrations for the most common bacterial strains of cerebral infections in both plasma and brain tissue, even in non-inflamed brain tissue. CSF concentrations would highly underestimate the target site activity of meropenem beyond the blood-brain barrier.