Mechanisms for Linezolid-Induced Anemia and Thrombocytopenia

Bernstein, Wendy B.; Trotta, Richard F.; Rector, James T.; Tjaden, Jeffrey; Barile, Anthony

doi:10.1345/aph.1c361

Cited by 156 publications

(125 citation statements)

References 12 publications

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“…Furthermore, no drug-related changes in vital signs or in clinical chemistry, urinalysis, or hematology values were observed. This confirms the fact that linezolid is well tolerated (5), even in cancer patients (25), and only a few adverse effects were reported (3,29).…”

Section: Discussionsupporting

confidence: 81%

Lack of Pharmacokinetic Interaction between Linezolid and Antacid in Healthy Volunteers

Grunder¹,

Zysset-Aschmann²,

Vollenweider³

et al. 2006

Antimicrob Agents Chemother

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Several antibiotics show significant pharmacokinetic interactions when they are given orally concomitantly with antacids. The objective of this study was to evaluate the effects of antacid (containing magnesium) on the pharmacokinetics of linezolid. A single dose of 600 mg linezolid was given orally alone and 10 min after administration of the antacid Maalox 70mVal, which contains 600 mg magnesium hydroxide and 900 mg aluminum hydroxide, to nine healthy males and nine healthy females in a crossover and randomized study. Linezolid plasma concentrations were determined by high-performance liquid chromatography, and pharmacokinetic parameters were calculated for both treatments. . However, a significant sex difference was observed for AUC, C max , V/F, and CL/F; and these differences could be almost completely explained by the differences in body weight between males and females. No clinically relevant adverse effects were detected under either condition. The coadministration of antacids had no effect on the pharmacokinetics of linezolid. This demonstrates that the oral absorption of linezolid was not affected by the presence of antacids containing magnesium hydroxide and aluminum hydroxide. Antacids can be safely administered together with linezolid.

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Section: Discussionsupporting

confidence: 81%

Lack of Pharmacokinetic Interaction between Linezolid and Antacid in Healthy Volunteers

Grunder¹,

Zysset-Aschmann²,

Vollenweider³

et al. 2006

Antimicrob Agents Chemother

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“…In those studies, tedizolid was also without hematopoietic toxicity at exposures up to 4 to 7 times the human-equivalent exposure, whereas linezolid toxicity was evident at drug levels comparable to the corresponding humanequivalent exposure (25,56,57). Hematopoietic effects of linezolid are believed to be the result of MPS inhibition in bone marrow cells (2,25,56,58). In the clinical setting, results from two phase 3 trials conducted in patients (n ϭ 1,333) with acute bacterial skin and skin structure infections indicated that tedizolid given at 200 mg once daily for 6 days resulted in a lower incidence of adverse changes in hematologic parameters, in particular platelets, than that with linezolid given at 600 mg twice daily for 10 days.…”

Section: Discussionmentioning

confidence: 99%

Nonclinical and Pharmacokinetic Assessments To Evaluate the Potential of Tedizolid and Linezolid To Affect Mitochondrial Function

Flanagan

McKee

Das

et al. 2015

Antimicrob Agents Chemother

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e Prolonged treatment with the oxazolidinone linezolid is associated with myelosuppression, lactic acidosis, and neuropathies, toxicities likely caused by impairment of mitochondrial protein synthesis (MPS). To evaluate the potential of the novel oxazolidinone tedizolid to cause similar side effects, nonclinical and pharmacokinetic assessments were conducted. In isolated rat heart mitochondria, tedizolid inhibited MPS more potently than did linezolid (average [؎ standard error of the mean] 50% inhibitory concentration [IC 50 ] for MPS of 0.31 ؎ 0.02 M versus 6.4 ؎ 1.2 M). However, a rigorous 9-month rat study comparing placebo and high-dose tedizolid (resulting in steady-state area under the plasma concentration-time curve values about 8-fold greater than those with the standard therapeutic dose in humans) showed no evidence of neuropathy. Additional studies explored why prolonged, high-dose tedizolid did not cause these mitochondriopathic side effects despite potent MPS inhibition by tedizolid. Murine macrophage (J774) cell fractionation studies found no evidence of a stable association of tedizolid with eukaryotic mitochondria. Monte Carlo simulations based on population pharmacokinetic models showed that over the course of a dosing interval using standard therapeutic doses, free plasma concentrations fell below the respective MPS IC 50 in 84% of tedizolid-treated patients (for a median duration of 7.94 h) and 38% of linezolid-treated patients (for a median duration of 0 h). Therapeutic doses of tedizolid, but not linezolid, may therefore allow for mitochondrial recovery during antibacterial therapy. The overall results suggest that tedizolid has less potential to cause myelosuppression and neuropathy than that of linezolid during prolonged treatment courses. This, however, remains a hypothesis that must be confirmed in clinical studies.

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“…5 Taking into account that peripheral blood cells were reduced in such short term (30 min) in our study, we consider as less likely that this is a result of bone marrow suppression. Yet, further research is needed to find the real mechanism.…”

Section: Discussionmentioning

confidence: 69%

“…[2][3][4] Reversible myelosuppression and immunemediated toxicity have been suggested as potential explanations for this observation. 3,5,6 In the current era, obesity seems to acquire an epidemic profile, especially in developed countries. Published evidence suggests that the outcome of infections may be associated with body mass index distribution.…”

Section: Introductionmentioning

confidence: 99%

Immediate hematological toxicity of linezolid in healthy volunteers with different body weight: a phase I clinical trial

et al. 2012

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Linezolid is an important therapeutic option for infections from multi-drug resistant Gram-positive pathogens. However, prolonged linezolid treatment (414 days) is considered to increase the risk of hematological adverse events. We aimed to evaluate the hematological safety profile of an i.v. single dose of linezolid in healthy volunteers of different body weight. We conducted a phase I clinical trial involving 20 healthy male Chinese volunteers that received an i.v. single dose of linezolid (600 mg). The study participants were assigned to two groups: low-weight (LW) group: 50 kg obody weight p55 kg and high-weight (HW) group: X80 kg. A significant decrease in the hemoglobin (Hb) levels and red blood cell (RBC) count was observed at the end of administration of the study drug in both groups. White blood cell (WBC) count was simultaneously decreased in the HW group. In the LW group, Hb levels and RBC count were also significantly decreased at 5, 7 and 24 h. In the HW group, both values were significantly decreased at 5 h. At 48 h all values were normal. The observed decreases were numerically higher in the LW group compared with the HW group. Yet, no statistical significance was noted. No difference was observed in the platelet count in both the groups. Our findings suggest that linezolid-associated hematological toxicity may also occur shortly after the i.v. administration of the drug in both LW and HW healthy volunteers. Early initiated continuous monitoring of hematological values and linezolid dosage adjustment for body weight are recommended.

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Mechanisms for Linezolid-Induced Anemia and Thrombocytopenia

Cited by 156 publications

References 12 publications

Lack of Pharmacokinetic Interaction between Linezolid and Antacid in Healthy Volunteers

Lack of Pharmacokinetic Interaction between Linezolid and Antacid in Healthy Volunteers

Nonclinical and Pharmacokinetic Assessments To Evaluate the Potential of Tedizolid and Linezolid To Affect Mitochondrial Function

Immediate hematological toxicity of linezolid in healthy volunteers with different body weight: a phase I clinical trial

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