Therapeutic drug monitoring may improve safety outcomes of long-term treatment with linezolid in adult patients

Abstract

Prolonged treatment with linezolid may cause toxicity. The purpose of this study was to define pharmacodynamic thresholds for improving safety outcomes of linezolid. We performed a retrospective study of patients who had trough (C(min)) and peak (C(max)) plasma levels measured during prolonged linezolid treatment. Dosage adjustments were performed when C(min) ≥10 mg/L and/or AUC₂₄ ≥400 mg/L · h. Patients were divided into two subgroups according to the absence or presence of co-treatment with rifampicin (the linezolid group and the linezolid + rifampicin group, respectively). Data on demographic characteristics, disease, microbiology and haematochemical parameters were collected and outcomes in relation to drug exposure were compared between groups. A total of 45 patients were included. Dosage adjustments were needed in 40% versus 0% of patients in the linezolid group (n = 35) versus the linezolid + rifampicin group (n = 10), respectively. Patients in the linezolid group had either significantly higher C(min) [3.71 mg/L (1.43-6.38) versus 1.37 mg/L (0.67-2.55), P < 0.001] or AUC₂₄ [212.77 mg/L · h (166.67-278.42) versus 123.33 mg/L · h (97.36-187.94), P < 0.001]. Thrombocytopenia appeared in 51.4% versus 0% of cases in the linezolid group versus the linezolid + rifampicin group, respectively. In 33.3% of those patients who were experiencing thrombocytopenia, therapeutic drug monitoring (TDM)-guided dosage reductions allowed recovery from toxicity and prosecution of therapy with good outcome. A logistic regression model for thrombocytopenia estimated a probability of 50% in the presence of C(min) of 6.53 mg/L and/or of AUC₂₄ of 280.74 mg/L · h. Maintenance over time of C(min) between 2 and 7 mg/L and/or of AUC₂₄ between 160 and 300 mg/L · h may be helpful in improving safety outcomes while retaining appropriate efficacy in adult patients receiving prolonged linezolid treatment.