Thrombocytopenia and anemia caused by a persistent high linezolid concentration in patients with renal dysfunction

Tsuji, Yasuhiro; Hiraki, Yoichi; Matsumoto, Kana; Mizoguchi, Akiko; Kobayashi, Tsutomu; Sadoh, Shinichi; Morita, Kunihiko; Kamimura, Hidetoshi; Karube, Yoshiharu

doi:10.1007/s10156-010-0080-6

Cited by 87 publications

(83 citation statements)

References 21 publications

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“…Although the level of renal clearance of linezolid is less than 30%, the early phase of sepsis is often a hypermetabolic condition leading to increased renal blood flow, glomerular filtration rate (GFR), renal creatinine clearance, and clearance of renally eliminated drugs (11) and it could explain the progressive decrease in C min by increasing the values of eGF presented in Table 3. In addition, recent data have shown higher levels of linezolid (12,13) and a higher toxicity (14,15) in patients with renal failure, suggesting that renal function impacts linezolid clearance. The risk of thrombocytopenia within the first 10 days of linezolid therapy is Ͻ10% (16).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…It would be reasonable that linezolid clearance is decreased in patients with low glomerular filtration. Tsuji et al [86] showed that the linezolid concentration was significantly higher than the predicted concentration in three patients with glomerular filtration <40 mL/min, and severe thrombocytopenia developed as the linezolid concentration increased. These findings have recently been confirmed in a study that included 30 patients [87].…”

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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“…29) In contrast, patients with renal dysfunction that received this dosage reached a C max of 200 µM and developed thrombocytopenia. 14) In this study, we therefore chose to utilize a maximum LZD concentration of 200 µM; however, even at this concentration LZD was not cytotoxic towards platelets (Fig. 1), indicating that the clinical application of this antimicrobial does not enhance platelet destruction.…”

Section: Discussionmentioning

confidence: 99%

“…7) Of these, the incidence of thrombocytopenia is particularly high (7.4-64.7%), [7][8][9][10][11] and the onset of this condition can lead to the discontinuation of LZD treatment. Recent clinical studies demonstrated that risk factors for LZD-induced thrombocytopenia include treatment for >14 consecutive days, 12,13) renal dysfunction, 8,9,14) and chronic liver disease. 15,16) The primary causes of thrombocytopenia can be broadly categorized into two mechanisms: increased consumption/ destruction or reduced production of platelets.…”

mentioning

confidence: 99%

Linezolid-Induced Thrombocytopenia Is Caused by Suppression of Platelet Production <i>via</i> Phosphorylation of Myosin Light Chain 2

Tajima

Kato

Matsumoto

et al. 2016

Biological & Pharmaceutical Bulletin

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Linezolid (LZD) is an antimicrobial that is commonly used for treatment of vancomycin-resistantEnterococci and methicillin-resistant Staphylococcus aureus infections. However, the development of thrombocytopenia, one of the most frequent adverse side effects of this antimicrobial, can lead to discontinuation of LZD treatment. While clinical studies indicate that risk factors for the development of LZD-induced thrombocytopenia include treatment for >14 consecutive days, renal dysfunction, and chronic liver disease, the fundamental mechanism governing the pathogenesis of this disorder remains unclear. In this study, we aimed to elucidate the mechanism of LZD-induced thrombocytopenia by investigating the impact of LZD treatment on platelet destruction and production using rat platelet-rich plasma (PRP) and human immortalized cell lines, respectively. Compared to the control population, an increase in lactate dehydrogenase release was not detected upon exposure of rat PRP to varying concentrations of LZD, indicating that this compound is not cytotoxic towards platelets. Meanwhile, LZD treatment resulted in a significant dose-dependent increase in the proliferation of HEL human erythroleukemia and MEG-01 human megakaryoblast cells in vitro, but did not influence the differentiation of these cell lines. Lastly, LZD treatment yielded elevated levels of phosphorylation of myosin light chain 2 (MLC2), which regulates platelet release, in MEG-01 cells. Based on these results, we speculate that LZD induces thrombocytopenia by promoting MLC2 phosphorylation and thereby suppressing the release of platelets from mature megakaryocytes. These findings provide the first insight into the mechanism of LZD-mediated thrombocytopenia and may facilitate the development of strategies to treat and/or prevent this disease.

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Thrombocytopenia and anemia caused by a persistent high linezolid concentration in patients with renal dysfunction

Cited by 87 publications

References 21 publications

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

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?

Linezolid-Induced Thrombocytopenia Is Caused by Suppression of Platelet Production <i>via</i> Phosphorylation of Myosin Light Chain 2

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