Risk factors for target non-attainment during empirical treatment with beta-lactam antibiotics in critically ill patients

Purpose: Risk factors for beta-lactam antibiotic underdosing in critically ill patients have not been described in large-scale studies. The objective of this study was to describe pharmacokinetic/pharmacodynamic (PK/PD) target non-attainment envisioning empirical dosing in critically ill patients and considering a worst-case scenario as well as to identify patient characteristics that are associated with target non-attainment. Methods: This analysis uses data from the DALI study, a prospective, multi-centre pharmacokinetic point-prevalence study. For this analysis, we assumed that these were the concentrations that would be reached during empirical dosing, and calculated target attainment using a hypothetical target minimum inhibitory concentration (MIC), namely the susceptibility breakpoint of the least susceptible organism for which that antibiotic is commonly used. PK/PD targets were free drug concentration maintained above the MIC of the suspected pathogen for at least 50 and 100 of the dosing interval respectively (50 and 100 f T >MIC). Multivariable analysis was performed to identify factors associated with inadequate antibiotic exposure. Results: A total of 343 critically ill patients receiving eight different ?-lactam antibiotics were included. The median (interquartile range) age was 60 (47-73) years, APACHE II score was 18 (13-24). In the hypothetical situation of empirical dosing, antibiotic concentrations remained below the MIC during 50 and 100 of the dosing interval in 66 (19.2 ) and 142 (41.4 ) patients respectively. The use of intermittent infusion was significantly associated with increased risk of non-attainment for both targets; creatinine clearance was independently associated with not reaching the 100 f T >MIC target. Conclusions: This study found that-in empirical dosing and considering a worst-case scenario-19 and 41 of the patients would not achieve antibiotic concentrations above the MIC during 50 and 100 of the dosin