A 10‐Year Experience of Therapeutic Drug Monitoring (<scp>TDM</scp>) of Linezolid in a Hospital‐wide Population of Patients Receiving Conventional Dosing: Is there Enough Evidence for Suggesting <scp>TDM</scp> in the Majority of Patients?

Pea, Federico; Cojutti, Pier Giorgio; Baraldo, Massimo

doi:10.1111/bcpt.12797

Cited by 69 publications

(52 citation statements)

References 32 publications

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“…Our study indicated that decreased renal function was an influential factor for linezolid‐induced thrombocytopenia, which was also in line with previously published studies . The increased odds of thrombocytopenia in patients with renal dysfunction were explained by previous studies showing that the increased blood concentration of linezolid‐induced by impaired renal function increases the risk of thrombocytopenia . However, the cut‐off value of CLcr as a risk factor varied among studies as follows: <60 mL/min, <50 mL/min or <30 mL/min .…”

Section: Discussionsupporting

confidence: 89%

Risk factors for linezolid‐induced thrombocytopenia in patients without haemato‐oncologic diseases

Choi

Lee

Chang

et al. 2018

Basic Clin Pharma Tox

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This study aimed to describe the occurrence and to evaluate the predictive factors of thrombocytopenia caused by parenteral linezolid in hospitalised patients without haemato-oncologic diseases. Using electronic medical records, a retrospective safety evaluation was performed among all hospitalised adult patients who received parenteral linezolid therapy between January 2005 and June 2016. Of all identified 264 patients with an average age of 63.4 (SD 15.8) years, thrombocytopenia occurred at a rate of 29.2% after an average of 11.2 (SD 7.4) days of the initiation of linezolid therapy. Significant predictive factors for thrombocytopenia included the duration of linezolid therapy longer than or equal to 7 days (adjusted odds ratios [ORs] 7.25, 19.51 and 28.80; 95% confidence intervals [CIs] 1.92-27.38, 4.76-79.95 and 6.48-127.92 for 7-13 days, 14-20 days and ≥21 days, respectively; P < 0.01 for all values), baseline platelet count <150 × 10 /mm (adjusted OR, 5.08; 95% CI, 2.06-12.55; P < 0.001), creatinine clearance <30 mL/min (adjusted OR, 4.19; 95% CI, 1.59-11.06; P = 0.004) and concurrent low-dose aspirin therapy (adjusted OR, 2.99; 95% CI, 1.26-7.08; P = 0.013). Baseline platelet count less than 150 × 10 /mm was an independent predictor of early-onset (≤6 days) thrombocytopenia (adjusted OR, 5.07; 95% CI, 1.46-17.58; P = 0.011). Closer monitoring of platelet count is required in patients who receive parenteral linezolid therapy for 7 days or more, and have low baseline platelet counts or impaired renal function.

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Section: Discussionsupporting

confidence: 89%

Risk factors for linezolid‐induced thrombocytopenia in patients without haemato‐oncologic diseases

Choi

Lee

Chang

et al. 2018

Basic Clin Pharma Tox

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“…Multiple postapproval population PK studies using data obtained from infected patients have consistently found renal function to be one of the most important predictors of linezolid CL (8,23,(32)(33)(34). Furthermore, we have previously demonstrated an association between renal impairment (creatinine clearance, Ͻ40 ml/ min) and a linezolid C min of Ͼ7 mg/liter (adjusted odds ratio [aOR], 3.05; 95% CI, 2.23 to 4.15), which is consistent with the findings by Morata and colleagues at the same eGFR threshold (aOR, 4.27; 95% CI, 1.36 to 13.43) (26,27).…”

Section: Discussionsupporting

confidence: 89%

“…Total daily doses of 300 to 1,800 mg/day were evaluated in increments between 150 and 300 mg in order to reflect pragmatic dose adjustments using the available formulations. Target C min values of Ͼ2 mg/liter for efficacy and Ͼ8 mg/liter for toxicity were used to reflect current practice in centers with TDM (27). A linezolid C min of Ͼ8 mg/liter has been associated with Ն50% odds of thrombocytopenia or decrease in platelet precursor cells in prior analyses (21,(23)(24)(25).…”

Section: Methodsmentioning

confidence: 99%

“…Linezolid trough concentrations above 7 to 8 mg/liter have been consistently associated with greater odds of developing thrombocytopenia (21)(22)(23)(24)(25). Furthermore, renal impairment has been identified as a significant risk factor for elevated linezolid trough concentrations in real-world clinical studies (26,27). Thus, observational data indicate that patients with renal impairment are at a higher risk for both supratherapeutic linezolid exposure and toxicity, which suggests that dose modification, or at least more frequent monitoring, may be necessary in this patient population.…”

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confidence: 99%

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Reappraisal of Linezolid Dosing in Renal Impairment To Improve Safety

Crass

Cojutti

Pai

et al. 2019

Antimicrob Agents Chemother

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Linezolid is administered as a fixed dose to all patients despite evidence of increased exposure and myelosuppression in renal impairment. The objectives of these studies were to assess the risk of thrombocytopenia with standard-dose linezolid in renal impairment and to identify an alternate dosing strategy. In study 1, data from adult patients receiving linezolid for Ն10 days were retrospectively reviewed to determine the frequency of thrombocytopenia in patients with and without renal impairment. Time-to-event analyses were performed using Cox proportional-hazards models. In study 2, population pharmacokinetic modeling was employed to build covariatestructured models using an independent data set of linezolid concentrations obtained during routine therapeutic drug monitoring (TDM). Monte Carlo simulations were performed to identify linezolid dosing regimens that maximized attainment of therapeutic trough concentrations (2 to 8 mg/liter) across various renal-function groups. Toxicity analysis (study 1) included 341 patients, 133 (39.0%) with renal impairment. Thrombocytopenia occurred more frequently among patients with renal impairment (42.9% versus 16.8%; P Ͻ 0.001), and renal impairment was independently associated with this toxicity in multivariable analysis (adjusted hazard ratio [aHR], 2.37; 95% confidence interval [CI], 1.52 to 3.68). Pharmacokinetic analyses (study 2) included 1,309 linezolid concentrations from 603 adult patients. Age, body surface area, and estimated glomerular filtration rate (eGFR) were identified as covariates of linezolid clearance. Linezolid dose reductions improved the probability of achieving optimal exposures in simulated patients with eGFR values of Ͻ60 ml/min. Thrombocytopenia occurs more frequently in patients with renal impairment receiving standard linezolid doses. Linezolid dose reduction and trough-based TDM are predicted to mitigate this treatment-limiting toxicity.

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“…However, results of studies investigating dose adjustment in obese patients under clinical conditions do not yet exist. The fraction of enterococci resistant to linezolid is currently reported to be 1.6% worldwide [46] and the rate is increasing [47][48][49]. In this context, therapeutic drug monitoring is recommended [50,51].…”

Section: Discussionmentioning

confidence: 99%

Linezolid Concentrations in Plasma and Subcutaneous Tissue are Reduced in Obese Patients, Resulting in a Higher Risk of Underdosing in Critically Ill Patients: A Controlled Clinical Pharmacokinetic Study

Simon

Busse

Petroff

et al. 2020

JCM

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Background: Linezolid is used for the treatment of soft tissue infections in critically ill patients. However, data for characterizing the pharmacokinetics (PK) and assessing whether effective concentrations are reached at the target site are lacking. We hypothesized that current dosing regimens do not lead to effective concentrations in the plasma and interstitial fluid (ISF) of subcutaneous tissue in obese patients. Methods: As a controlled clinical model, critically ill obese and non-obese patients undergoing intra-abdominal surgery received 600 mg linezolid as a single infusion. Concentrations in the plasma and microdialysate from the ISF of subcutaneous tissue were determined up to 8 h after dosing. Pharmacokinetic analysis was performed by non-compartmental methods. As a therapeutic target, we used f AUC/MIC > 80. Results: Fifteen obese (BMI: 48.7 ± 11.2 kg/m 2 ) and 15 non-obese (23.9 ± 2.1 kg/m 2 ) patients were analyzed. AUC 0-8 in ISF decreased by −1.69 mg*h/L (95% CI: −2.59 to −0.79, p < 0.001) for every 10 kg increase in weight. PK in obese patients were characterized by lower maximal plasma concentrations (median 3.8 vs. 8.3 mg/L, p < 0.001) and a higher volume of distribution (41.0 vs. 30.8 L, p < 0.001), and the therapeutic target was not reached for MIC ≥ 1 mg/L in ISF and ≥ 2 mg/L in plasma. Conclusions: Increasing the weight led to a decrease of linezolid concentrations in the plasma and subcutaneous tissue. The current dosing regimen does not seem to produce sufficient concentrations to kill bacteria with MIC ≥ 2 mg/L, especially as empirical antimicrobial therapy in critically ill obese patients.

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A 10‐Year Experience of Therapeutic Drug Monitoring (TDM) of Linezolid in a Hospital‐wide Population of Patients Receiving Conventional Dosing: Is there Enough Evidence for Suggesting TDM in the Majority of Patients?

Cited by 69 publications

References 32 publications

Risk factors for linezolid‐induced thrombocytopenia in patients without haemato‐oncologic diseases

Risk factors for linezolid‐induced thrombocytopenia in patients without haemato‐oncologic diseases

Reappraisal of Linezolid Dosing in Renal Impairment To Improve Safety

Linezolid Concentrations in Plasma and Subcutaneous Tissue are Reduced in Obese Patients, Resulting in a Higher Risk of Underdosing in Critically Ill Patients: A Controlled Clinical Pharmacokinetic Study

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