Early adequate linezolid concentrations and clinical outcomes in confirmed Gram-positive infections: the role of therapeutic drug monitoring.

Abstract

Background and objectives: Due to the unpredictable exposure of linezolid with a standard dosing regimen, therapeutic drug monitoring (TDM) has been recommended to guide it despite limited evidence on clinical endpoints. The primary objective was to determine whether achieving therapeutic linezolid concentrations at the first TDM measurement is associated with clinical cure. Microbiological eradication and 7 day and 30 day mortality were also assessed.

Methods: We conducted a retrospective study in a cohort of patients with confirmed Gram-positive (Enterococcus/Staphylococcus spp.) infections and undergoing TDM. A steady-state linezolid trough concentration (Cmin,ss) of 2-8 mg/L was considered therapeutic. A multivariable logistic regression model assessed predictive factors associated with clinical cure.

Results: Four hundred patients (median age 68 years, 66.5% male) were included. Infections were mainly intra-abdominal (29.3%), skin/soft tissue or bone/joint (25.5%) and respiratory (21%). At first measurement only 34% of patients reached the therapeutic range, with 34.5% below range and 31.5% above range. Clinical cure rate was 76.3% and 30 day all-cause mortality was 20%. Multivariable logistic regression showed that achieving therapeutic Cmin,ss significantly increased the likelihood of clinical cure (OR 1.78, 95% CI 1.02-3.19). Conversely, a higher Charlson index, liver cirrhosis and sepsis/septic shock requiring ICU admission were risk factors for failure. Other clinical outcomes were not independently related to Cmin,ss.

Conclusions: This study suggests that achieving early therapeutic linezolid concentrations is associated with a higher likelihood of clinical cure and highlights the limitations of an initial standard dosing. In this scenario, an early TDM may help to identify patients out-of-range who need guided dosing to ensure the achievement of pharmacokinetic/pharmacodynamic targets. Further prospective studies are needed to assess the impact of TDM on survival, microbiological outcomes and cost-effectiveness.