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

J Antimicrob Chemother. 2018 Nov 1;73(11):3087-3094. doi: 10.1093/jac/dky314.


Objectives: To describe the achievement of unbound β-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>4×MIC, respectively. Dose reduction was indicated in 17.3% of cases for an upper PK/PD threshold of 100% fT>10×MIC. Higher protein bound β-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>4×MIC (OR 2.47 and 3.05, respectively; P < 0.01).

Conclusions: Measuring unbound concentrations of β-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Anti-Bacterial Agents / pharmacokinetics*
  • Anti-Bacterial Agents / therapeutic use*
  • Ceftriaxone / pharmacokinetics
  • Ceftriaxone / therapeutic use
  • Critical Illness / therapy
  • Drug Monitoring*
  • Female
  • Humans
  • Logistic Models
  • Male
  • Meropenem / pharmacokinetics
  • Meropenem / therapeutic use
  • Microbial Sensitivity Tests
  • Middle Aged
  • Piperacillin / pharmacokinetics
  • Piperacillin / therapeutic use
  • Prospective Studies
  • Treatment Outcome
  • beta-Lactams / pharmacokinetics*
  • beta-Lactams / therapeutic use*


  • Anti-Bacterial Agents
  • beta-Lactams
  • Ceftriaxone
  • Meropenem
  • Piperacillin