Reappraisal of linezolid dosing in renal impairment to improve safety

Linezolid is administered as a fixed dose to all patients despite evidence of increased exposure and myelosuppression in renal impairment. The objectives of these studies were to assess the risk of thrombocytopenia with standard-dose linezolid in renal impairment and to identify an alternate dosing strategy. In study 1, data from adult patients receiving linezolid for 10 days were retrospectively reviewed to determine the frequency of thrombocytopenia in patients with and without renal impairment. Time-to-event analyses were performed using Cox proportional-hazards models. In study 2, population pharmacokinetic modeling was employed to build covariatestructured models using an independent data set of linezolid concentrations obtained during routine therapeutic drug monitoring (TDM). Monte Carlo simulations were performed to identify linezolid dosing regimens that maximized attainment of therapeutic trough concentrations (2 to 8 mg/liter) across various renal-function groups. Toxicity analysis (study 1) included 341 patients, 133 (39.0%) with renal impairment. Thrombocytopenia occurred more frequently among patients with renal impairment (42.9% versus 16.8%; P<0.001), and renal impairment was independently associated with this toxicity in multivariable analysis (adjusted hazard ratio [aHR], 2.37; 95% confidence interval [CI], 1.52 to 3.68). Pharmacokinetic analyses (study 2) included 1,309 linezolid concentrations from 603 adult patients. Age, body surface area, and estimated glomerular filtration rate (eGFR) were identified as covariates of linezolid clearance. Linezolid dose reductions improved the probability of achieving optimal exposures in simulated patients with eGFR values of <60 ml/min. Thrombocytopenia occurs more frequently in patients with renal impairment receiving standard linezolid doses. Linezolid dose reduction and trough-based TDM are predicted to mitigate this treatment-limiting toxicity.