Therapeutic drug monitoring of beta-lactam antibiotics in the critically ill: direct measurement of unbound drug concentrations to achieve appropriate drug exposures

Objectives: To describe the achievement of unbound beta-lactam antibiotic concentration targets in a therapeutic drug monitoring (TDM) programme in critically ill patients, and the factors associated with failure to achieve a target concentration. Patients and methods: Plasma samples and clinical data were obtained for analysis from a single centre prospectively. Unbound concentrations of ceftriaxone, cefazolin, meropenem, ampicillin, benzylpenicillin, flucloxacillin and piperacillin were directly measured using ultracentrifugation. Factors associated with the achievement of pharmacokinetic/pharmacodynamic (PK/PD) targets or negative clinical outcomes were evaluated with binomial logistic regression. Results: TDM data from 330 patients, and 369 infection episodes, were included. The range of doses administered was 99.4%+/- 45.1% relative to a standard daily dose. Dose increases were indicated in 33.1% and 63.4% of cases to achieve PK/PD targets of 100% fT(>MIC) and 100% fT(>4xMIC), respectively. Dose reduction was indicated in 17.3% of cases for an upper PK/PD threshold of 100% fT(>10xMIC). Higher protein bound beta-lactams (ceftriaxone and benzylpenicillin) had better therapeutic target attainment (P < 0.01), but were prone to excessive dosing. Augmented renal clearance (calculated CLCR > 130 mL/min) increased the odds of failure to achieve 100% fT(>MIC) and 100% fT(>4xMIC) (OR 2.47 and 3.05, respectively; P < 0.01). Conclusions: Measuring unbound concentrations of beta-lactams as part of a routine TDM programme is feasible and demonstrates that a large number of critically ill patients do not achieve predefined PK/PD targets. The clinical significance of this finding is unknown due to the lack of correlation between PK/PD findings and clinical outcomes.