Brain Microdialysis Study of Meropenem in Two Patients with Acute Brain Injury

Adier

et al. 2014

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The distribution of metronidazole in the central nervous system has only been described based on cerebrospinal fluid data. However, extracellular fluid (ECF) concentrations may better predict its antimicrobial effect and/or side effects. We sought to explore by microdialysis brain ECF metronidazole distribution in patients with acute brain injury. Four brain-injured patients monitored by cerebral microdialysis received 500 mg of metronidazole over 0.5 h every 8 h. Brain dialysates and blood samples were collected at steady state over 8 h. Probe recoveries were evaluated by in vivo retrodialysis in each patient for metronidazole. Metronidazole and OH-metronidazole were assayed by high-pressure liquid chromatography, and a noncompartmental pharmacokinetic analysis was performed. Probe recovery was equal to 78.8% ؎ 1.3% for metronidazole in patients. Unbound brain metronidazole concentration-time curves were delayed compared to unbound plasma concentration-time curves but with a mean metronidazole unbound brain/plasma AUC 0 -ratio equal to 102% ؎ 19% (ranging from 87 to 124%). The unbound plasma concentration-time profiles for OH-metronidazole were flat, with mean average steady-state concentrations equal to 4.0 ؎ 0.7 g ml ؊1 . This microdialysis study describes the steady-state brain distribution of metronidazole in patients and confirms its extensive distribution. Metronidazole, a nitroimidazole antibiotic, is useful for treating infections by Bacteroides spp. and many anaerobic bacteria. Since metronidazole is supposed to penetrate extensively into central nervous system (CNS), it has been described in literature as being responsible for both peripheral (1) and central (2-6) neurotoxicity, especially after a prolonged use of metronidazole (7). In both cases, symptoms and lesions on magnetic resonance imaging may spontaneously regress after discontinuation of treatment. While the pathogenesis as yet remains unclear, the most likely hypothesis is an axonal swelling due to metronidazoleinduced vasogenic edema, which could be linked to an impairment of vitamin B 1 action, because of metronidazole conversion to a thiamine analog (8). Thus, characterizing the distribution of metronidazole in cerebral tissue may contribute to managing the dosing regimen in order to prevent side effects while preserving maximal antibacterial efficiency.Differences in anatomy, enzymatic activity or bulk-flow exist between blood-brain-barrier (BBB) and blood-cerebrospinal fluid (CSF) barrier (9), which could result in differences in drug distribution between the CSF and brain extracellular fluid (ECF). Current metronidazole doses rely on a few studies that show an extensive distribution of metronidazole into the CSF (10-12). However, most of the previous CSF pharmacokinetic studies of metronidazole used nonspecific microbiological assays that cannot distinguish parent drug from metabolites (13-16) and at present no study has explored the distribution of metronidazole in the brain ECF.Intracerebral microdialysis is the state-of-the-art in ...

Section: Discussionmentioning

confidence: 48%

Metronidazole and Hydroxymetronidazole Central Nervous System Distribution: 1. Microdialysis Assessment of Brain Extracellular Fluid Concentrations in Patients with Acute Brain Injury

Adier

et al. 2014

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“…For each patient, in vivo probe recovery was determined using retrodialysis by drug over 2.5 h at the end of the experiment, as previously described (12,13). The next cefotaxime injection was delayed to perform the recovery estimation.…”

Section: Methodsmentioning

confidence: 99%

“…The compartmental analysis was performed in two steps as previously described (12). Briefly, unbound plasma drug concentration-time data were first analyzed using a twocompartment model.…”

Section: Methodsmentioning

confidence: 99%

“…In humans, feasibility issues of brain microdialysis restrict its use, and this technique concerns only patients who require surgery for brain tumor resection (10) or cerebral metabolism monitoring in neurointensive care units (11). The main advantage in intracerebral microdialysis is to measure continuously brain unbound concentrations as a function of time; the comparison of these brain concentrations with unbound plasma concentrations may provide information on drug transport across the BBB (12).…”

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confidence: 99%

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Microdialysis Study of Cefotaxime Cerebral Distribution in Patients with Acute Brain Injury

Grégoire

et al. 2013

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Central nervous system (CNS) antibiotic distribution was described mainly from cerebrospinal fluid data, and only few data exist on brain extracellular fluid concentrations. The aim of this study was to describe brain distribution of cefotaxime (2 g/8 h) by microdialysis in patients with acute brain injury who were treated for a lung infection. Microdialysis probes were inserted into healthy brain tissue of five critical care patients. Plasma and unbound brain concentrations were determined at steady state by high-performance liquid chromatography. In vivo recoveries were determined individually using retrodialysis by drug. Noncompartmental and compartmental pharmacokinetic analyses were performed. Unbound cefotaxime brain concentrations were much lower than corresponding plasma concentrations, with a mean cefotaxime unbound brain-to-plasma area under the curve ratio equal to 26.1 ؎ 12.1%. This result was in accordance with the brain input-to-brain output clearances ratio (CL in,brain /CL out,brain ). Unbound brain concentrations were then simulated at two dosing regimens (4 g every 6 h or 8 h), and the time over the MICs (T>MIC) was estimated for breakpoints of susceptible and resistant Streptococcus pneumoniae strains. T>MIC was higher than 90% of the dosing interval for both dosing regimens for susceptible strains and only for 4 g every 6 h for resistant ones. In conclusion, brain distribution of cefotaxime was well described by microdialysis in patients and was limited.

“…More recently, microdialysis was developed to measure brain extracellular fluid (ECF) concentrations of drugs as a better way to characterize CNS distribution (2). However, brain microdialysis studies in humans are relatively complex to perform, and limited data have been published (3,4). Interestingly, recent experimental studies have shown differences between CSF and ECF concentrations for acetaminophen and quinidine in rats (5,6).…”

mentioning

confidence: 99%

Metronidazole and Hydroxymetronidazole Central Nervous System Distribution: 2. Cerebrospinal Fluid Concentration Measurements in Patients with External Ventricular Drain

Adier

et al. 2014

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dThis study explored metronidazole and hydroxymetronidazole distribution in the cerebrospinal fluid (CSF) of brain-injured patients. Four brain-injured patients with external ventricular drain received 500 mg of metronidazole over 0.5 h every 8 h. CSF and blood samples were collected at steady state over 8 h, and the metronidazole and hydroxymetronidazole concentrations were assayed by high-pressure liquid chromatograph. A noncompartmental analysis was performed. Metronidazole is distributed extensively within CSF, with a mean CSF to unbound plasma AUC 0 -ratio of 86% ؎ 16%. However, the concentration profiles in CSF were mostly flat compared to the plasma profiles. Hydroxymetronidazole concentrations were much lower than those of metronidazole both in plasma and in CSF, with a corresponding CSF/unbound plasma AUC 0 -ratio of 79% ؎ 16%. We describe here for the first time in detail the pharmacokinetics of metronidazole and hydroxymetronidazole in CSF.T he blood-brain barrier (BBB) and blood-CSF barrier (BCSFB) protect the brain from neurotoxic substances and control drug distribution. Central nervous system (CNS) distribution studies are essential to predict drug's efficacy and/or side effects. Antibiotics may be used for the treatment of CNS infections but may also induce undesirable excitatory side effects. Drug distribution in the CNS has been traditionally assessed based on cerebrospinal fluid (CSF) concentrations after lumbar puncture or external ventricular drainage. However, these studies present a number of limits that have recently been reviewed (1). More recently, microdialysis was developed to measure brain extracellular fluid (ECF) concentrations of drugs as a better way to characterize CNS distribution (2). However, brain microdialysis studies in humans are relatively complex to perform, and limited data have been published (3, 4). Interestingly, recent experimental studies have shown differences between CSF and ECF concentrations for acetaminophen and quinidine in rats (5, 6). In fact, despite similarities, BBB and BSCFB present structural differences (2) that may lead to distinct brain ECF and CSF concentration-versus-time profiles. Comparisons between ECF and CSF concentrations have been reported in animals (1, 5, 6) and, to our knowledge, in one previous study on carbamazepine in humans (7). Metronidazole, a nitroimidazole antibiotic, is indicated in cerebromeningeal infections by anaerobic bacteria (8), but it is also known to induce peripheral and central side effects (9-12). Our goal was to perform a CSF distribution study in patients and to compare CSF concentrations to the ECF concentrations determined by brain microdialysis in an accompanying study (13), using metronidazole and OH-metronidazole, an active metabolite of metronidazole, as representative antibiotics with extensive CNS distribution. MATERIALS AND METHODSPatients. This study was performed at the University Hospital of Poitiers (France) and was approved by the local ethics committee (CPP OUEST III, protocol 2008-003311-12 Drug ...