Variability of linezolid concentrations after standard dosing in critically ill patients: a prospective observational study

Zöller, Michael; Maier, Bárbara; Hornuß, Cyrill; Neugebauer, Christina; Döbbeler, Gundula; Nagel, Dorothea; Holdt, Lesca M.; Bruegel, Mathias; Weig, Thomas; Grabein, B.; Frey, Lorenz; Teupser, Daniel; Vogeser, Michael; Zander, Johannes

doi:10.1186/cc13984

Cited by 102 publications

(70 citation statements)

References 53 publications

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“…is recommended for all adult patients by the product information and has been included in treatment guidelines. However, recent studies have observed a high variability of linezolid blood concentrations, with partly insufficient concentrations in critically ill patients treated by this standard scheme (13)(14)(15)(16)(17). We recently observed that 19 of 30 critically ill patients had insufficient concentrations and that 2 of them reached potentially toxic serum concentrations (13).…”

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confidence: 95%

Predictors of Inadequate Linezolid Concentrations after Standard Dosing in Critically Ill Patients

Taubert

Zöller

Maier

et al. 2016

Antimicrob Agents Chemother

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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 [AUC 12 ]/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.)

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confidence: 95%

Predictors of Inadequate Linezolid Concentrations after Standard Dosing in Critically Ill Patients

Taubert

Zöller

Maier

et al. 2016

Antimicrob Agents Chemother

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“…Furthermore, other studies indicate the large variations in the levels of the different classes of antibiotics used in ICU: cefepime [29], meropenem [30], piperacillin [14], linezolid [31][32][33], sulfamethoxazole/trimethoprim [34], fluconazole [13,35], flucloxacillin [36], and ciprofloxacin [9,10,37]. In addition to the extensive inter-individual variation, intra-individual variation was observed for piperacillin [14] and linezolid [33].…”

Section: Impact Of Pathophysiological Changes On the Antimicrobial Thmentioning

confidence: 99%

The use of liquid chromatography-tandem mass spectrometry for therapeutic drug monitoring of antibiotics in cancer patients

El‐Najjar

Gessner

2017

Clinical Chemistry and Laboratory Medicine (CCLM)

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Cancer remains a leading cause of mortality and morbidity worldwide. In addition to organ failure, the most frequent reasons for admission of cancer patients to intensive care units (ICU) are: infections and sepsis. As critically ill, the complexity of the health situation of cancer patients renders the standard antimicrobial regimen more complex and even inadequate which results in increased mortality rates. This is due to pathophysiological changes in the volume of distribution, increased clearance, as well as to organ dysfunction. While in the former cases a decrease in drug efficacy is observed, the hallmark of the latter one is overdosing leading to increased toxicity at the expense of efficacy. Furthermore, an additional risk factor is the potential drug-drug interaction between antibiotics and antineoplastic agents. Therefore, therapeutic drug monitoring (TDM) is a necessity to improve the clinical outcome of antimicrobial therapy in cancer patients. To be applied in routine analysis the method used for TDM should be cheap, fast and highly accurate/sensitive. Furthermore, as ICU patients are treated with a cocktail of antibiotics the method has to cover the simultaneous analysis of antibiotics used as a first/second line of treatment. The aim of the current review is to briefly survey the pitfalls in the current antimicrobial therapy and the central role of TDM in dose adjustment and drug-drug interaction's evaluation. A major section is dedicated to summarize the currently published analytical methods and to shed light on the difficulties and potential problems that can be encountered during method development.

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“…Elevated LNZ plasma trough concentrations (C min values) have been reported in patients with renal or hepatic dysfunction, critically ill patients, renal transplant cases who experienced thrombocytopenia after starting treatment with linezolid compared with values measured in healthy volunteers. 9 The rate of therapy failure and adverse effects may be in part explained by a high variability of linezolid serum concentration in patients.…”

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Association between serum linezolid concentration and haematological toxic effects: a longitudinal study

2017

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Background: Linezolid is a commonly used antibiotic and reported various drug related adverse effects mainly haematological toxicity like thrombocytopenia, leukopenia and anaemia. But a significant association between linezolid plasma concentration and drug related adverse effects are not documented yet. This longitudinal observational study aims to study the incidence of drug related haematological toxicities and its association with serum Linezolid concentration and also evaluate the clinical outcome.Methods: After obtaining informed consent, each patient (18-50years) was given linezolid (600mg/12hourly), and evaluated for haematological (haemoglobin, platelets, WBCs), renal (as serum creatinine), and hepatic (as serum transaminases status), together with an assessment of drug C min values. These evaluations were repeated once a week or in concomitance with the development of an adverse event up to the end of linezolid therapy. The parametric dependent ‘t’ test was applied (p<0.05) and normality of data were performed by Kolmogorov Smirnov test, follows normal distribution.Results: There was significant reduction in platelet count and haemoglobin value seen from baseline till end of treatment (p<0.001) and there was 13% reduction in WBC count in all patients on day 14 when compared to baseline (p<0.001) indicating haematological toxicity according to WHO toxicity grading scale. All the patients (n=8; 26.6%) who developed drug related haematological toxicity also showed comparable increase in plasma linezolid concentration (C min) >10mg/L at the end of 14days.Conclusions: The capability to monitor plasma linezolid concentration (C min; trough value) once a week may lead to a significant improvement in clinical use of the drug both in terms of efficacy and tolerability as the study observed that there is association between linezolid concentration and risk of developing drug related haematological toxicity.

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Variability of linezolid concentrations after standard dosing in critically ill patients: a prospective observational study

Cited by 102 publications

References 53 publications

Predictors of Inadequate Linezolid Concentrations after Standard Dosing in Critically Ill Patients

Predictors of Inadequate Linezolid Concentrations after Standard Dosing in Critically Ill Patients

The use of liquid chromatography-tandem mass spectrometry for therapeutic drug monitoring of antibiotics in cancer patients

Association between serum linezolid concentration and haematological toxic effects: a longitudinal study

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