The aim of this study was to evaluate the biopharmaceutical behavior of colistin methanesulfonate (CMS) with special focus on colistin presystemic formation after CMS nebulization in rats. CMS was administered (15 mg ⅐ kg ؊1 of body weight) either intravenously for systemic pharmacokinetic studies (n ‫؍‬ 6) or as an intratracheal nebulization for systemic pharmacokinetic studies (n ‫؍‬ 5) or for CMS and colistin concentration measurements in epithelial lining fluid (ELF) at 30, 120, and 240 min after nebulization (n ‫؍‬ 14). CMS and colistin concentrations were determined by a new liquid chromatography (LC)-tandem mass spectrometry (MS/MS) assay. Pharmacokinetic parameters were estimated by noncompartmental analysis. CMS and colistin pharmacokinetic data were consistent with previously published values when comparisons were possible. The fraction of the CMS dose converted systematically into colistin after intravenous CMS administration was estimated to be 12.5% on average. After CMS nebulization it was estimated that about two-thirds of the dose was directly absorbed within the systemic circulation, whereas one-third was first converted into active colistin, which was eventually absorbed. As a consequence, the colistin area under curve (AUC) reflecting systemic availability was about 4-fold greater after CMS intratracheal nebulization (607 ؎ 240 g ⅐ min ⅐ ml ؊1 ) than after CMS intravenous administration (160 ؎ 20 g ⅐ min ⅐ ml ؊1 ). CMS concentrations in ELF at 30 min and 120 min postnebulization were very high (in the order of several mg/ml) due to the limited volume of ELF but were considerably reduced at 240 min. Although lower (15% ؎ 5% at 120 min) in relative terms, colistin concentrations in ELF could be high enough for being active against microorganisms following CMS nebulization.

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 ...

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.