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Cerebrospinal fluid penetration and pharmacodynamic exposure of meropenem prophylactically administered to neurosurgical patients

Abstract number: P1248

Ikawa K., Tsumura R., Morikawa N., Ikeda K., Shibukawa M., Iida K., Kurisu K.

Objectives: Meropenem is frequently used for the treatment and prophylaxis of bacterial meningitis. However, the drug's distribution within the site of action is poorly understood. This study examined the penetration and pharmacodynamic exposure of meropenem into cerebrospinal fluid (CSF).

Methods: Meropenem (0.5 g every 8 h) was prophylactically administered to six patients who underwent neurosurgery and external lumbar drainage for the management of cerebrovascular diseases. Lumbar CSF and venous blood samples were obtained at the end of the infusion (0.5 h) and 1, 1.5, 2.5, 4.5, and 8 h thereafter. Pharmacokinetic data in CSF and plasma were estimated noncompartmentally, analysed using a 3-compartment pharmacokinetic model, and used for a Monte Carlo simulation with MIC data of clinical isolates in Japan.

Results: Noncompartmental pharmacokinetic analysis demonstrated that the observed maximum concentration was 0.66 ±0.17 (mean ± SD) mg/L at 3.00±1.22 h in CSF and 29.50±6.54 mg/L at 0.5 h in plasma, and the CSF/plasma ratio was 0.024±0.011. The area under the drug concentration-time curve (AUC 0–8 h) was 3.76±0.75 mg·h/L in CSF and 35.76±6.15 mg·h/L in plasma, and the CSF/plasma ratio was 0.109±0.035. The Monte Carlo simulation combined with compartmental pharmacokinetic modeling showed that the probabilities of achieving the bacteriostatic exposure target in CSF (30% of the time above the MIC) for 0.5 g every 8 h (0.5-h infusion) were 99.8% against a Streptococcus pneumoniae population (MIC50 = 0.06 mg/L; MIC90 = 0.5 mg/L) and 99.6% against a Haemophilus influenzae population (MIC50 = 0.12 mg/L; MIC90 = 0.5 mg/L), respectively. The prophylactic regimen of 0.5 g every 8 h was considered to provide sufficient bacteriostatic exposure in CSF for the two major meningitis pathogens.

Conclusion: These results expand our knowledge of the rate and extent of meropenem penetration into the cerebrospinal fluid and space, and provide a pharmacokinetic-pharmacodynamic rationale for design of a meropenem regimen to prevent bacterial meningitis.

Session Details

Date: 19/04/2008
Time: 00:00-00:00
Session name: 18th European Congress of Clinical Microbiology and Infectious Diseases
Subject:
Location: Barcelona, Spain
Presentation type:
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