Rifampin concentrations in various compartments of the human brain: a novel method for determining drug levels in the cerebral extracellular space - PubMed (original) (raw)

Rifampin concentrations in various compartments of the human brain: a novel method for determining drug levels in the cerebral extracellular space

T Mindermann et al. Antimicrob Agents Chemother. 1998 Oct.

Abstract

Antimicrobial therapy for brain infections is notoriously difficult because of the limited extent of knowledge about drug penetration into the brain. Therefore, we determined the penetration of rifampin into various compartments of the human brain, including the cerebral extracellular space (CES). Patients undergoing craniotomy for resection of primary brain tumors were given a standard dose of 600 mg of rifampin intravenously before the operation. A microdialysis probe (10 by 0.5 mm) was inserted into the cortex distantly from the resection and was perfused with two different rifampin solutions. Rifampin concentrations in the CES were calculated by the no-net-flux method. Intraoperatively, samples were taken from brain tumor tissue, perifocal tissue, and normal brain tissue in the case of pole resections. Rifampin concentrations in the various samples were determined by using a bioassay with Sarcinea lutea. In the various compartments, rifampin concentrations were highest within tumors (1.37 +/- 1.34 microg/ml; n = 8), followed by the perifocal region (0.62 +/- 0.67 microg/ml; n = 8), the CES (0.32 +/- 0.11 microg/ml; n = 6), and normal brain tissue (0.29 +/- 0.15 microg/ml; n = 7). Rifampin concentrations in brain tumors do not adequately reflect concentrations in normal brain tissue or in the CES. Rifampin concentrations in the CES, as determined by microdialysis, are the most reproducible, and the least scattered, of the values for all compartments evaluated. Rifampin concentrations in all compartments exceed the MIC for staphylococci and streptococci. However, CES concentrations may be below the MICs for some mycobacterial strains.

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Figures

FIG. 1

FIG. 1

Rifampin in the CES of patient 6. The determination of the concentration of rifampin in the CES in one patient illustrates the principle of the no-net-flux method. The probe was first perfused with a 0.5-μg/ml solution of rifampin at a constant flow rate of 3 μl/min, resulting in 180 μl of dialysate after 1 h. It was then perfused with a 1.0-μg/ml solution of rifampin under the same conditions. The concentrations of rifampin in the perfusates and the dialysates were determined together with those in the other samples and were used for calculation. The concentration of rifampin in the CES was calculated from the perfusates’ loss or gain in rifampin. The intercept with the zero line indicates equilibrium, i.e., equal concentrations inside and outside the microdialysis probe. At this intercept, the concentration of rifampin in the CES (0.24 μg/ml) was determined from the x axis. This represents the average concentration of rifampin in the CES over a period of 2 h.

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