Linezolid Dosing in Patients With Liver Cirrhosis: Standard Dosing Risk Toxicity

Abstract

Background: Limited data regarding altered linezolid pharmacokinetics in patients with liver cirrhosis are available. The objective of this study was to evaluate the pharmacokinetics, efficacy and safety of linezolid in cirrhotic patients. Methods: A case–control 1:1 study of patients undergoing linezolid therapeutic drug monitoring was conducted between January 2015 and June 2017. Cases with liver cirrhosis were matched with controls by age, body weight, comorbidities, renal function, and intensive care unit (ICU) admission. Results: Fifty-two patients were included, 26 in each group. Patients with Child–Pugh Scores A, B, and C were 1 (3.8%), 13 (50.0%), and 12 (46.2%), respectively. Cases had higher median linezolid trough plasma concentrations than controls [20.6 (17.4) versus 2.7 (11.3); P < 0.001)] and more frequently achieved an optimal pharmacodynamic index [26 (100%) versus 16 (61.5%); P = 0.002]. In addition, potentially toxic concentrations and treatment discontinuation due to overexposure and hematological toxicity were also more frequently seen in cirrhotic patients. Overall clinical cure rate was high (67.4%), and in-hospital mortality was 28.8%. No differences in clinical outcomes were observed between both groups. Conclusions: Linezolid showed a high clinical cure rate. Nevertheless, plasma concentrations and treatment discontinuation due to hematological toxicity were higher in cirrhotic patients. Liver cirrhosis may influence linezolid pharmacokinetics and question the use of standard doses. Therapeutic drug monitoring of linezolid would be valuable in these patients.

Population Pharmacokinetics and Dosage Optimization of Linezolid in Patients with Liver Dysfunction

“…The study also showed that liver cirrhosis was an independent risk factor for thrombocytopenia. Luque et al (22) investigated the relationship between linezolid standard dose and risky toxicity in patients with liver cirrhosis and found that patients were more likely to achieve supratherapeutic concentrations and to suffer severe thrombocytopenia. The reason may be a reduced nonrenal clearance (26,27).…”

“…This is consistent with the findings of a previous PPK/PD study of Japanese patients (21), which included 4 patients with severe cirrhosis. Another study (22) about the risk of standard dose of linezolid for patients with liver cirrhosis suggested that a reduced dose at 600 mg/24 h was preferred. What is more, 400 mg, q24 h was sufficient to achieve the target (AUC 0 -24 /MIC Ն80) (probability, 97.9%) against pathogens with an MIC of 2 g/ml for patients with LD with a PTA of Յ20%.…”

“…Sasaki et al (21) performed a population pharmacokinetics analysis among Japanese patients and revealed that renal function and severe liver cirrhosis significantly affected the pharmacokinetics of linezolid, although only 4 liver cirrhosis patients were included. Luque et al (22) demonstrated that patients with liver cirrhosis were more likely to be exposed to supratherapeutic concentrations and suffer adverse events when they received standard-dose linezolid (600 mg/12 h) than patients with LD who did not use linezolid.…”

Accumulation of Major Linezolid Metabolites in Patients with Renal Impairment

“…This review specifically highlighted the lack of recommendations for linezolid dose adjustment in renal impairment despite the elevated myelosuppression risk. Luque et al (17) demonstrated that standard doses of linezolid in patients with moderate to severe cirrhosis resulted in concentrations of Ͼ8 mg/liter, with thrombocytopenia observed in 41.7% to 66.7% of patients. Our previously described assay methodology therefore provides research groups with an opportunity to profile linezolid and metabolite concentrations and better characterize this cumulative risk potential in specific populations.…”

Initially Reduced Linezolid Dosing Regimen to Prevent Thrombocytopenia in Hemodialysis Patients

“…These are likely due to the early intervention via initial dose reduction to avoid linezolid overexposure, as patient demographics, baseline laboratory values, microorganisms, and the type of infection were not significantly different between the two groups. Other factors affecting the pharmacokinetics of linezolid include drug–drug interaction [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ], liver dysfunction [ 25 , 26 ], and critical illness with/without acute kidney injury [ 27 , 28 ]. In our study, there were no episodes of linezolid co-administration with rifampicin, omeprazole, amlodipine, amiodarone, or dexamethasone, and there were no differences in the population of patients co-administered with levothyroxine in both groups, indicative of a limited effect of drug–drug interactions.…”