Therapeutic Drug Monitoring of Linezolid: a Retrospective Monocentric Analysis

Pea, Federico; Furlanut, Mario; Cojutti, Pier Giorgio; Cristini, Francesco; Zamparini, Eleonora; Franceschi, Loretta; Viale, Pierluigi

doi:10.1128/aac.00177-10

Cited by 173 publications

(146 citation statements)

References 36 publications

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“…Therefore, treatment with a fixed dose may be questionable (6,11,22,26). The application of TDM for linezolid can help avoid under-or overexposure, which may occur in 30 to 40% of the cases (20). In this study, all patients had Mycobacterium tuberculosis isolates with a linezolid MIC of Յ0.5 mg/liter.…”

Section: Discussionmentioning

confidence: 99%

Dried Blood Spot Analysis for Therapeutic Drug Monitoring of Linezolid in Patients with Multidrug-Resistant Tuberculosis

Bolhuis

Koster

et al. 2012

Antimicrob Agents Chemother

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dLinezolid is a promising antimicrobial agent for the treatment of multidrug-resistant tuberculosis (MDR-TB), but its use is limited by toxicity. Therapeutic drug monitoring (TDM) may help to minimize toxicity while adequate drug exposure is maintained. Conventional plasma sampling and monitoring might be hindered in many parts of the world by logistical problems that may be solved by dried blood spot (DBS) sampling. The aim of this study was to develop and validate a novel method for TDM of linezolid in MDR-TB patients using DBS sampling. Plasma, venous DBS, and capillary DBS specimens were obtained simultaneously from eight patients receiving linezolid. A DBS sampling method was developed and clinically validated by comparing DBS with plasma results using Passing-Bablok regression and Bland-Altman analysis. This study showed that DBS analysis was reproducible and robust. Accuracy and between-and within-day precision values from three validations presented as bias and coefficient of variation (CV) were less than 17.2% for the lower limit of quantification and less than 7.8% for other levels. The method showed a high recovery of approximately 95% and a low matrix effect of less than 8.7%. DBS specimens were stable at 37°C for 2 months and at 50°C for 1 week. The ratio of the concentration of linezolid in DBS samples to that in plasma was 1.2 (95% confidence interval [CI], 1.12 to 1.27). Linezolid exposure calculated from concentrations DBS samples and plasma showed good agreement. In conclusion, DBS analysis of linezolid is a promising tool to optimize linezolid treatment in MDR-TB patients. An easy sampling procedure and high sample stability may facilitate TDM, even in underdeveloped countries with limited resources and where conventional plasma sampling is not feasible.

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Section: Discussionmentioning

confidence: 99%

Dried Blood Spot Analysis for Therapeutic Drug Monitoring of Linezolid in Patients with Multidrug-Resistant Tuberculosis

Bolhuis

Koster

et al. 2012

Antimicrob Agents Chemother

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“…Our results are in agreement with two recent studies about linezolid pharmacokinetics (PK). The first one analyzed the C min of linezolid in 92 patients, and 29% had a C min below the MIC 90 of linezolid (6). The second experiment was performed in 8 critically ill patients who received linezolid at 600 mg/12 h, and 50% of them had a linezolid C min Ͻ 1 mg/liter (8).…”

Section: Discussionmentioning

confidence: 99%

“…In a retrospective study of linezolid in a compassionate use program, a higher success rate was observed when concentrations remained above the MIC for the entire dosing interval and when AUC 24 /MIC values were 80 to 120 (5). Some recent data suggest that the linezolid trough plasma concentration (C min ), in some patients, is below the MIC 90 of linezolid for staphylococci (6).…”

mentioning

confidence: 99%

Risk Factors for a Low Linezolid Trough Plasma Concentration in Acute Infections

Morata

Cuesta

Rojas

et al. 2013

Antimicrob Agents Chemother

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Linezolid is an antibiotic with time-dependent activity, and both the percentage of time that plasma concentrations exceed the MIC and the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC 24 /MIC ratio) are associated with clinical response. The aim of this study was to analyze the linezolid trough plasma concentration (C min ) and to determine factors associated with a C min < 2 mg/liter and other clinically relevant thresholds. Characteristics of 78 patients receiving 600 mg/12 h of linezolid with a C min determination at the steady state and within the first 10 days of treatment were retrospectively reviewed. Concentrations were measured using high-pressure liquid chromatography. Univariate and multivariate analysis were performed to identify risk factors of low C min . A total of 29.5% of patients had a C min < 2 mg/liter. The percentage was significantly higher in patients with an estimated glomerular filtration (eGF) > 80 ml/min, in intensive care unit (ICU) patients, and in patients with an infection due to Staphylococcus aureus. The independent predictors of C min < 2 mg/liter were an eGF > 80 ml/min (odds ratio [OR], 10; 95% confidence interval [CI], 2.732 to 37.037; P ‫؍‬ 0.001) and infection due to S. aureus (OR, 5.906; 95% CI, 1.651 to 21.126; P ‫؍‬ 0.006). A linezolid C min of <2 mg/liter was found in 29.5% of cases, and the risk was significantly higher among those with an eGF > 80 ml/min and in infections due to S. aureus. In patients with severe sepsis, a loading dose or continuous infusion and drug monitoring could improve the pharmacodynamic parameters associated with linezolid efficacy.L inezolid belongs to a family of antimicrobials (oxazolidinones) that inhibit bacterial protein synthesis by preventing the fusion of 30S and 50S ribosomal subunits (1). During the last 10 years, linezolid has been widely used with good clinical results for the treatment of skin and soft tissue infections or nosocomial and health care-related pneumonia (2, 3). Linezolid has time-dependent activity, and the best predictors of its efficacy are the percentage of time that plasma concentrations exceed the MIC and the area under the concentrationtime curve over 24 h in the steady state divided by the MIC (AUC 24 /MIC ratio) (4). In a retrospective study of linezolid in a compassionate use program, a higher success rate was observed when concentrations remained above the MIC for the entire dosing interval and when AUC 24 /MIC values were 80 to 120 (5). Some recent data suggest that the linezolid trough plasma concentration (C min ), in some patients, is below the MIC 90 of linezolid for staphylococci (6).The aim of our study was to analyze the linezolid trough plasma concentration in a consecutive series of patients with an acute infection and to determine how often trough concentrations were Ͻ2 mg/liter (MIC 90 of linezolid for Staphylococcus aureus) and other clinically relevant thresholds (0.5, 1, and 4 mg/liter). MATERIALS AND METHODSThe linezolid trough plasma concent...

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“…Some data suggest that linezolid inhibits its own metabolism [80], therefore prolonged treatment is associated with a progressive increase in serum concentrations that are associated with haematological toxicity [81,82]. The linezolid toxic trough is not well defined but supposedly should not be >8 mg/L (ideally 2-7 mg/L), and therapeutic drug monitoring (TDM) should probably be performed in certain circumstances [79,81]. A recent study analysed the trough concentrations in consecutive patients and found a mean trough of 9 mg/L in patients who developed haematological toxicity compared with 4 mg/L in those without toxicity [82].…”

Section: Prolonged Use Of Linezolidmentioning

confidence: 99%

Treatment options for methicillin-resistant Staphylococcus aureus (MRSA) infection: Where are we now?

Edwards

Andini

Esposito

et al. 2014

Journal of Global Antimicrobial Resistance

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Therapeutic Drug Monitoring of Linezolid: a Retrospective Monocentric Analysis

Cited by 173 publications

References 36 publications

Dried Blood Spot Analysis for Therapeutic Drug Monitoring of Linezolid in Patients with Multidrug-Resistant Tuberculosis

Dried Blood Spot Analysis for Therapeutic Drug Monitoring of Linezolid in Patients with Multidrug-Resistant Tuberculosis

Risk Factors for a Low Linezolid Trough Plasma Concentration in Acute Infections

Treatment options for methicillin-resistant Staphylococcus aureus (MRSA) infection: Where are we now?

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