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Objectives: Insufficient linezolid levels, which are associated with a poorer outcome, are often observed in ICU patients who receive standard dosing. Although strategies to overcome these insufficient levels have been discussed, appropriate alternative dosing regimens remain to be identified., Methods: Various infusion regimens (1200-3600 mg/day; q6h, q8h, q12h and continuous) were simulated in 67 000 ICU patients. The probability of attaining pharmacodynamic targets ( T >MIC ≥85%, AUC/MIC ≥100, cumulative fraction of response for Staphylococcus aureus and Enterococcus spp., PTA for an MIC of 0.5-4 mg/L) as well as the avoidance of toxic concentrations and concentrations constantly below the MIC (lack of antibiotic effect) or inside a mutant selection window (resistance development) were evaluated., Results: Best target attainment according to T >MIC was observed for continuous infusions, followed by q6h, q8h and q12h. A substantially reduced target attainment was observed in patients with acute respiratory distress syndrome (ARDS). In patients without ARDS, 1200 mg/day was insufficient irrespective of the regimen, while a dose of 1400 mg/day administered q6h or by continuous infusions provided an acceptable target attainment (e.g. cumulative fraction of response with regards to T >MIC  ≥93%). Higher rates of potentially toxic trough concentrations (28% versus 12%) and concentrations constantly inside the mutant selection window (15% versus <0.1%) were observed with continuous infusions compared with q6h infusions (1400 mg/day, patients without ARDS)., Conclusions: Irrespective of the regimen, 1200 mg/day linezolid might be insufficient for the treatment of ICU patients. Patients without ARDS might particularly benefit from q6h infusions with increased daily doses (e.g. 1400 mg/day)., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Adequate linezolid blood concentrations have been shown to be associated with an improved clinical outcome. Our goal was to assess new predictors of inadequate linezolid concentrations often observed in critically ill patients. Fifty-two critically ill patients with severe infections receiving standard dosing of linezolid participated in this prospective observational study. Serum samples (median, 32 per patient) were taken on four consecutive days, and total linezolid concentrations were quantified. Covariates influencing linezolid pharmacokinetics were identified by multivariate analysis and a population pharmacokinetic model. Target attainment (area under the concentration-time curve over 12 h [AUC12]/MIC ratio of >50; MIC = 2 mg/liter) was calculated for both the study patients and a simulated independent patient group (n = 67,000). Target attainment was observed for only 36% of the population on both days 1 and 4. Independent covariates related to significant decreases of linezolid concentrations included higher weight, creatinine clearance rates, and fibrinogen and antithrombin concentrations, lower concentrations of lactate, and the presence of acute respiratory distress syndrome (ARDS). Linezolid clearance was increased in ARDS patients (by 82%) and in patients with elevated fibrinogen or decreased lactate concentrations. In simulated patients, most covariates, including fibrinogen and lactate concentrations and weight, showed quantitatively minor effects on target attainment (difference of ≤9% between the first and fourth quartiles of the respective parameters). In contrast, the presence of ARDS had the strongest influence, with only ≤6% of simulated patients reaching this target. In conclusion, the presence of ARDS was identified as a new and strong predictor of insufficient linezolid concentrations, which might cause treatment failure. Insufficient concentrations might also be a major problem in patients with combined alterations of other covariate parameters. (This study has been registered at ClinicalTrials.gov under registration number NCT01793012.)., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Background: Although therapeutic drug monitoring (TDM) for antibiotics in critically ill patients is recommended by expert panels, no commercial tests are available for most antibiotics. Therefore, we previously developed a multianalyte method for the quantification of piperacillin, tazobactam, cefepime, meropenem, ciprofloxacin and linezolid in serum. However, limited stability data were available, and the relevant studies did not address the coefficients of variation of the methods applied, which may be important for verifying the storage dependency of the observed effects. Here we aimed to evaluate the storage effects of antibiotics by applying a novel evaluation protocol. Methods: Serum-based test samples were aliquoted and stored at room temperature, 4 °C, -20 °C or -80 °C for up to 180 days. Using an innovative evaluation protocol (considering the coefficient of variation, p-value, and criterion of monotony of observed changes), we assessed whether relevant changes (defined as ≥ 15% in comparison with baseline) were storage dependent (defined as substantial changes). Results: Storage at -80 °C for up to 180 days did not lead to substantial changes for any analyte. In contrast, storage at -20 °C induced substantial decreases after ≥ 7 days for piperacillin, tazobactam, cefepime and meropenem; after 90 days at -20 °C, only ≤ 23% of the initial concentrations were found for these parameters. No substantial changes were observed for linezolid and ciprofloxacin at any storage condition. All of the observed substantial changes were monotonic decreases. Conclusions: We recommend a storage temperature of -80 °C for β-lactam antibiotics. The applied evaluation protocol yielded conclusive results and may be generally useful for stability studies. [ABSTRACT FROM AUTHOR]

Background: Recent studies have demonstrated highly variable blood concentrations of piperacillin, tazobactam, cefepime, meropenem, ciprofloxacin and linezolid in critically ill patients with a high incidence of sub-therapeutic levels. Consequently, therapeutic drug monitoring (TDM) of these antibiotics has to be considered, requiring robust and reliable routine analytical methods. The aim of the present work was to develop and validate a multi-analyte ultra high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method for the simultaneous quantification of the above mentioned antibiotics. Methods: Sample preparation included a manual protein precipitation step followed by two-dimensional ultra high performance liquid chromatography (2D-UHPLC). Corresponding stable isotope-labeled substances were used as internal standards for all of the analytes, with the exception of tazobactam. The injected sample volume was 7 μL. The run time was 5.0 min. Results: Inaccuracy was ≤8% and imprecision coefficient of variation (CV) was <9% for all analytes. Only minor matrix effects and negligible carry-over was observed. The method was found to be robust during the validation period. Conclusions: We were able to develop a reliable 2D-UHPLC-MS/MS method addressing analytes with highly heterogeneous physico-chemical properties. The novel assay may be an efficient tool for an optimized process workflow in clinical laboratories for important antibiotics in regards to TDM. [ABSTRACT FROM AUTHOR]

Background: Linezolid serum concentrations have been shown to be highly variable in critically ill patients with often sub-therapeutic drug levels regarding minimal inhibitory concentrations for relevant pathogens. Consequently, therapeutic drug monitoring of linezolid must be considered, requiring a reliable and convenient analytical method. We therefore developed and validated an LC-MS/MS method applying isotope dilution internal standardization and on-line solid phase extraction for serum linezolid quantification. Methods: Sample preparation was based on protein precipitation and on-line solid phase extraction with two-dimensional liquid chromatography and column switching. Three-fold deuterated linezolid was used as the internal standard. The method was validated involving two separate LC-MS/MS systems covering the concentration range of 0.13-32 mg/L. The run time was 4 min. Results: Validation revealed good analytical performance, with inaccuracy <6% and imprecision of <7.3% (CV) for six quality control samples (0.38-16.0 mg/L). The method was found to be robust during the validation process and during a pharmacokinetic study so far involving 600 samples. Comparative measurements on two LC-MS/MS systems revealed close agreement. Conclusions: This LC-MS/MS assay described herein is a convenient, robust and reliable method for linezolid quantification in serum which can be routinely applied using different LC-MS/MS systems. The method can be used for clinical studies and subsequent TDM of linezolid. [ABSTRACT FROM AUTHOR]

The article presents a case study of a patient with septic shock and multiple organ failure, characterized by excessive inflammatory responses. An initial laparotomy showed an ischaemic bowel with peritonitis, and the patient was given intravenous meropenem and segmental resection of the jejunum and colon. The patient was given with linezolid and meropenem. The case demonstrated the effect of cytokine adsorber treatment on antibiotic concentrations.