Impact of high plasma concentrations of linezolid in Taiwanese adult patients— therapeutic drug monitoring in improving adverse drug reactions

Cheng, C. H.; Wu, Chih‐Yu; Kuo, Ching‐Hua; Wang, Chi-Chuan; Wang, Jann-Tay; Lin, Yen-Liang; Jhang, Ren-Shiang; Lin, Shu-Wen

doi:10.1016/j.jfma.2020.06.011

Cited by 20 publications

(27 citation statements)

References 28 publications

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“…Numerous clinical studies have evaluated the exposure–toxicity relationship of linezolid. A significantly higher linezolid trough concentration ( C min ) was observed in patients with thrombocytopaenia than in patients without thrombocytopaenia 41 . Nukui et al found that the thrombocytopaenia rate was significantly greater in patients with a linezolid C min > 7.5 μg/mL 28 .…”

Section: Discussionmentioning

confidence: 99%

Effect of renal function on the risk of thrombocytopaenia in patients receiving linezolid therapy: A systematic review and meta‐analysis

Shi

Xia

et al. 2021

Brit J Clinical Pharma

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The association of renal function and linezolid-induced thrombocytopenia (LIT) remains controversial. We performed a meta-analysis to determine whether impaired renal function is associated with an increased LIT risk. Methods:We conducted a systematic search of PubMed, EMBASE and the Cochrane Library from inception to February 2021 for eligible studies evaluating the relationship between renal function and LIT. Indictors of renal function included renal impairment (RI), severe RI, hemodialysis status, creatinine clearance rate (Ccr) and estimated glomerular filtration rate (eGFR). Unadjusted and adjusted estimates and 95% confidence intervals (CIs) were calculated separately using a random-effect model.Results: A total of 24 studies with 3580 patients were included in the meta-analysis. RI patients had an increased LIT risk compared to non-RI patients in both the unadjusted (OR 4.15; 95% Cl 2.85 to 6.03; I 2 =0%) and adjusted analyses (OR 4.15; 95% Cl 2.85 to 6.03; I 2 =0%). This association persisted in the subset of studies involving only patients receiving a fixed conventional dose (600 mg every 12 h) and other subgroup analyses by ethnicity, sample size and study quality. Moreover, the LIT risk was significantly higher in patients with severe RI and hemodialysis than in patients without severe RI and hemodialysis. The eGFR and Ccr were significantly lower in LIT patients than in non-LIT patients.Conclusions: Impaired renal function is associated with an increased risk of LIT. A reduced linezolid dose may be considered in RI patients at a low risk of treatment failure, ideally guided by therapeutic drug monitoring.

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Section: Discussionmentioning

confidence: 99%

Effect of renal function on the risk of thrombocytopaenia in patients receiving linezolid therapy: A systematic review and meta‐analysis

Shi

Xia

et al. 2021

Brit J Clinical Pharma

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“…Despite heterogeneity in the populations studied, a C min > 6-10 mg/L has consistently been associated with an increased risk of thrombocytopenia. [35][36][37][38][39][40] In a study of Taiwanese adults, 13 of 36 (36%) with linezolid concentrations available developed thrombocytopenia during treatment. 38 The median C min and AUC 24 were both significantly higher in the patients with thrombocytopenia (C min : 13.0 vs. 7.2 mg/L, P = 0.027; AUC 24 : 451 vs. 291 mg•h/L, P = 0.025) and C min was a significant predictor of thrombocytopenia on multivariable Cox regression.…”

Section: Linezolid and Thrombocytopeniamentioning

confidence: 99%

“…[35][36][37][38][39][40] In a study of Taiwanese adults, 13 of 36 (36%) with linezolid concentrations available developed thrombocytopenia during treatment. 38 The median C min and AUC 24 were both significantly higher in the patients with thrombocytopenia (C min : 13.0 vs. 7.2 mg/L, P = 0.027; AUC 24 : 451 vs. 291 mg•h/L, P = 0.025) and C min was a significant predictor of thrombocytopenia on multivariable Cox regression. 38 In a similar study among Chinese adults, linezolid C min was significantly higher in patients with thrombocytopenia (n = 31, median = 8.81 mg/L) compared with those without (n = 39, median = 2.88 mg/L, P < 0.0001).…”

Section: Linezolid and Thrombocytopeniamentioning

confidence: 99%

“…Of linezolid’s toxicities, exposure has been most consistently linked to development of thrombocytopenia, and the good correlation between AUC and C min has allowed for a C min ‐toxicity threshold to be defined. Despite heterogeneity in the populations studied, a C min > 6–10 mg/L has consistently been associated with an increased risk of thrombocytopenia 35–40 . In a study of Taiwanese adults, 13 of 36 (36%) with linezolid concentrations available developed thrombocytopenia during treatment 38 .…”

Section: Category 1: Drug Exposure‐toxicity Relationship Is Definedmentioning

confidence: 99%

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Too Much of a Good Thing: Defining Antimicrobial Therapeutic Targets to Minimize Toxicity

Downes

Goldman

2021

Clin Pharma and Therapeutics

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Antimicrobials are a common cause of drug toxicity. Understanding the relationship between systemic antimicrobial exposure and toxicity is necessary to enable providers to take a proactive approach to prevent undesired drug effects. When an exposure threshold has been defined that predicts drug toxicity, therapeutic drug monitoring (TDM) can be performed to assure drug exposure does not exceed the defined threshold. Although some antimicrobials have well-defined dose-dependent toxicities, many other exposure-toxicity relationships have either not been well-defined or, in some cases, not been evaluated at all. In this review, we examine the relationship between exposures and toxicities for antibiotic, antifungal, and antiviral agents. Furthermore, we classify these relationships into four categories: known association between drug exposure and toxicity such that clinical implementation of a specific exposure threshold associated with toxicity for TDM is supported (category 1), known association between drug exposure and toxicity but the specific exposure threshold associated with toxicity is undefined (category 2), association between drug exposure and toxicity has been suggested but relationship is poorly defined (category 3), and no known association between drug exposure and toxicity (category 4). Further work to define exposure-toxicity thresholds and integrate effective TDM strategies has the potential to minimize many of the observed antimicrobial toxicities.

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“…Additionally, in 2020, three independent groups documented that linezolid-related adverse events, namely thrombocytopenia, lactic acidosis, and hyponatremia, were more frequent in elderly patients and were associated with elevated linezolid trough concentrations [8][9][10]. Based on these findings, a reduction in linezolid doses has been proposed in patients at a high risk of drug overexposure to limit/prevent the risk of drug-related adverse events, especially when therapeutic drug monitoring (TDM) is not available [4][5][6][7][8][9][10][11][12][13][14][15]. Here, we describe our past 5-year experience with the TDM of linezolid with the aim of verifying whether these recommendations have been implemented in daily clinical practice, with a special focus on elderly patients.…”

Section: Introductionmentioning

confidence: 99%

Supra-therapeutic Linezolid Trough Concentrations in Elderly Patients: A Call for Action?

et al. 2020

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Background and Objective According to the drug label, linezolid dosage adjustments are not needed in geriatric patients. Nevertheless, clinical evidence suggests that elderly patients may benefit from the use of reduced linezolid doses to limit drug overexposure. Here, we aimed to describe the results of the last 5 years of therapeutic drug monitoring of linezolid in our institution with a special focus on elderly patients. Methods Linezolid therapeutic drug monitoring requests collected between January 2016 and June 2020 were considered. Linezolid trough concentrations were considered both as a continuous variable and as a categorical variable, clustering data according to the therapeutic range proposed by available literature (< 2, 2-8, and > 8 mg/L, respectively). Patients' age and sex were considered as categorical variables. Comparisons of linezolid trough concentrations between groups of patients stratified according to age were performed using an analysis of variance; comparisons in the frequency distributions were performed using the chi-squared test. Results From 2016 to 2020, we collected 3250 linezolid TDM requests. A highly significant, progressive increment in the linezolid trough concentrations was observed moving from patients aged < 50 years (5.8 ± 5.6 mg/L) to those aged > 90 years (16.6 ± 10.0 mg/L), with an overall increment of 30% per decade of age. Nearly 30%, 50%, and 65% of patients aged < 65 years, 65-80 years, and > 80 years, respectively, had supra-therapeutic linezolid trough concentrations at the first therapeutic drug monitoring assessment. This trend did not change significantly moving from 2016 to 2020. Conclusions Elderly patients given linezolid at the conventional 600-mg twice-daily dose might be at a high risk of being overexposed to treatment, eventually increasing their risk to experience drug-related hematological toxicity. Reduced linezolid dosing schemes should be potentially considered in elderly patients at a low risk of treatment failure, ideally guided by therapeutic drug monitoring.

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Impact of high plasma concentrations of linezolid in Taiwanese adult patients— therapeutic drug monitoring in improving adverse drug reactions

Cited by 20 publications

References 28 publications

Effect of renal function on the risk of thrombocytopaenia in patients receiving linezolid therapy: A systematic review and meta‐analysis

Effect of renal function on the risk of thrombocytopaenia in patients receiving linezolid therapy: A systematic review and meta‐analysis

Too Much of a Good Thing: Defining Antimicrobial Therapeutic Targets to Minimize Toxicity

Supra-therapeutic Linezolid Trough Concentrations in Elderly Patients: A Call for Action?

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