Therapeutic Drug Monitoring Can Improve Linezolid Dosing Regimens in Current Clinical Practice: A Review of Linezolid Pharmacokinetics and Pharmacodynamics

Abstract

Linezolid is an antibiotic used to treat infections caused by drug-resistant gram-positive organisms, including vancomycin-resistant Enterococcus faecium, multi-drug resistant Streptococcus pneumoniae, and methicillin-resistant Staphylococcus aureus. The adverse effects of linezolid can include thrombocytopenia and neuropathy, which are more prevalent with higher exposures and longer treatment durations. Although linezolid is traditionally administered at a standard 600 mg dose every 12 hours, the resulting exposure can vary greatly between patients and can lead to treatment failure or toxicity. The efficacy and toxicity of linezolid are determined by the exposure achieved in the patient; numerous clinical and population pharmacokinetics (popPK) studies have identified threshold measurements for both parameters. Several special populations with an increased need for linezolid dose adjustments have also been identified. Therapeutic Drug Monitoring (TDM) is a clinical strategy that assesses the response of an individual patient and helps adjust the dosing regimen to maximize efficacy while minimizing toxicity. Adaptive feedback control and model-informed precision dosing are additional strategies that use Bayesian algorithms and PK models to predict patient-specific drug exposure. TDM is a very useful tool for patient populations with sparse clinical data or known alterations in pharmacokinetics, including children, patients with renal insufficiency or those receiving renal replacement therapy, and patients taking co-medications known to interact with linezolid. As part of the clinical workflow, clinicians can use TDM with the thresholds summarized from the current literature to improve linezolid dosing for patients and maximize the probability of treatment success.

Accumulation of Major Linezolid Metabolites in Patients with Renal Impairment

“…Observational studies have suggested that the risk of myelosuppression is not only time dependent but also considerably higher in patients with renal impairment (4,5). However, limited data are available to determine the influence of kidney function on the pharmacokinetics of linezolid and its primary metabolites to support future therapeutic drug-monitoring (TDM) strategies targeted to reduce the risk of toxicity (6).…”

“…Standard curves were linear (r 2 Ն 0.99) for linezolid concentrations within 0.1 to 50 mg/liter and for concentrations of both metabolites within 0.1 to 25 mg/liter. Although concentrations should be reported in molar units, we report the concentrations of each analyte in the current work to permit direct comparison with prior literature (3,(6)(7)(8). The serum concentrations of linezolid and its two primary metabolites are provided in Table 1.…”

“…Linezolid trough concentrations of Ͼ7 to 8 mg/liter have been associated with an increased risk of myelosuppression (6). Rao et al (6) recently provided an excellent summary of existing pharmacokinetic and pharmacodynamic data in support of linezolid TDM. This review specifically highlighted the lack of recommendations for linezolid dose adjustment in renal impairment despite the elevated myelosuppression risk.…”

Treatment Considerations for CNS Infections Caused by Vancomycin-Resistant Enterococcus faecium: A Focused Review of Linezolid and Daptomycin

“…These can include the critically ill, those with renal dysfunction, those with obesity, pediatric patients, and patients receiving p-glycoprotein (P-gp) modulators (rifampin). 35,36…”

“…These can include the critically ill, those with renal dysfunction, those with obesity, pediatric patients, and patients receiving p-glycoprotein (P-gp) modulators (rifampin). 35,36 Serum trough concentrations (C min ) between 2 and 8 ng/ mL, with a peak concentration of 10 to 20 ng/mL, have been suggested as normal for linezolid. 33,37 Some evidence has failed to find a correlation between abnormal levels and adverse clinical outcomes.…”