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 AUC0–8 was 233.2 ± 42.7 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 (AUCbrain/AUCplasma) was 0.11 ± 0.06, which was more than 3 times higher than in CSF (0.03 ± 0.01), resulting in an AUCCSF/AUCbrain ratio of 0.41 ± 0.16 at steady state. After single-dose administration similar proportions were achieved (AUCbrain/AUCplasma = 0.09 ± 0.08; AUCCSF/AUCplasma = 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.

中文翻译：

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神经重症监护患者脑组织中美罗培南浓度超过 CSF 水平

背景 脑感染中抗生素暴露不足可能对临床结果产生不利影响。通常，脑脊液中的抗生素浓度用于估计脑靶水平。然而，超出血脑屏障的实际药理活性未结合药物浓度是未知的。目的比较神经重症监护患者血液、脑脊液和脑微透析液中美罗培南的浓度。患者和方法 在 12 名患有蛛网膜下腔出血的患者中，由于脑外感染，每 8 小时给予 2000 mg 美罗培南。在稳态 (n = 11) 和单剂量给药后 (n = 5) 测定血液、CSF 和脑微透析液中的美罗培南浓度。结果稳态时，血浆中游离AUC0-8为233.2±42.7 mg·h/L，7.8±1。脑脊液中为 9 mg·h/L，脑组织中为 26.6 ± 14.0 mg·h/L。脑组织穿透比 (AUCbrain/AUCplasma) 为 0.11 ± 0.06，比 CSF (0.03 ± 0.01) 高 3 倍以上，导致稳态时 AUCCSF/AUCbrain 比为 0.41 ± 0.16。单次给药后达到了相似的比例（AUCbrain/AUCplasma = 0.09 ± 0.08；AUCCSF/AUCplasma = 0.02 ± 0.00）。脑组织浓度与 CSF 浓度密切相关（R = 0.74，P < 0.001），但仅与血浆浓度适度相关（R = 0.51，P < 0.001）。对于 MIC 值≤16 mg/L，血浆和脑组织均达到杀菌阈值。在 CSF 中，只有 MIC 值≤1 mg/L 时才达到杀菌效果。结论 美罗培南对血浆和脑组织中最常见的脑感染菌株达到足够的杀菌浓度，即使在非炎症脑组织中也是如此。脑脊液浓度会高度低估美罗培南在血脑屏障之外的靶位活性。