Developments in the pharmacokinetic/pharmacodynamic index of linezolid: a step toward dose optimization using Monte Carlo simulation in critically ill patients

Abstract

Objectives: This study evaluated the efficacy of the pharmacokinetic/pharmacodynamic (PK/PD) index for increasing the success rate of linezolid treatment based on Monte Carlo simulation, and compared differences between the calculated PK/PD breakpoints and those defined by committee for critically ill patients with linezolid treatment.

Methods: A Monte Carlo simulation involving 10000 subjects was used to analyze the pharmacokinetic parameters and microbiological data of linezolid for an effectiveness evaluation at the corresponding AUC24/MIC values (area under the serum concentration-time curve over 24h/minimum inhibitory concentration).

Results: As the PK/PD index of linezolid increased from 80 to 120, the corresponding probability of target attainment (PTA) decreased from 99.91% to 18.97%, with a MIC of 2mg/l. Furthermore, the cumulative fraction of response (CFR) reached <90% for several pathogens at an AUC24/MIC of 100-120, revealing a relatively lower efficacy with recommended linezolid dosing.

Conclusions: These findings reveal that the target AUC24/MIC value of 80-120 requires further classification for more accurate assessment of the linezolid dose regimen. At a MIC of ≥2mg/l, the clinical outcome varies greatly for different AUC24/MIC values when applying the same dose of linezolid. In such cases, we suggest optimized adjustment of the linezolid dosage regimen.

Keywords: Critically ill patients; Dose optimization; Linezolid; Monte Carlo simulation; Pharmacokinetic/pharmacodynamic (PK/PD).