Therapeutic drug monitoring of beta-lactam antibiotics in the critically ill: direct measurements of unbound drug concentrations to achieve appropriate drug exposures.
Predicting antibiotic concentrations in ICU patients is highly challenging because of the large pharmacokinetic variability seen in this specific population [1, 2]. Using published data to predict protein binding may lead to important under- or overestimation of unbound beta-lactam concentrations in ICU patients . In view of the highly unpredictable antibiotic concentrations, therapeutic drug monitoring (TDM) of unbound beta-lactam antibiotic concentrations is a promising strategy to assist physicians in optimising antibiotic therapy.
Wong, et al . described the achievement of unbound beta-lactam antibiotic concentration targets in a TDM programme in ICU patients and described the factors associated with failure to achieve a target concentration.
Predefined PK/PD targets were:
- 100% fT>MIC and 100% fT>4xMIC. The upper limit of the therapeutic range was defined as
- 100% fT>10xMIC. Binomial logistic regression was used to assess the factors associated with target non-attainment.
Three hundred and thirty patients were evaluated:
- A dose increase was indicated in 33.1% to achieve the PK/PD target of 100% fT>MIC and in 63.4% to achieve 100% fT>4xMIC and dose reduction was indicated in 17.3% of the cases.
- Higher target attainment was seen with higher bound beta-lactam antibiotics while augmented renal clearance and prolonged infusion were identified as predictors of target non-attainment.
- There was no significant difference in the number of patients achieving the PK/PD targets after dose-adjustments based on the TDM programme.
While it is difficult to select a good PK/PD target given the inconsistent literature, the first condition to be fulfilled when a TDM programme is implemented is that the level of therapeutic concentrations, preferably at the focus of infection, is higher when compared to the level of therapeutic concentrations in the absence of a TDM programme. In this study, despite the use of a rational dose adjustment strategy, there was no significant increase in the level of target attainment. It is important to understand why increasing the dosing frequency or prolonging the duration of infusion did not led to the desired effect in this study.
Patients with low target attainment are likely to suffer from ARC. In this context, it is worth considering that administering drugs that are mainly renally-cleared in patients with a good renal function may not lead to a proportional increase in target attainment, even if prolonged infusion is used.
TAKE HOME MESSAGES
- While measuring unbound beta-lactam antibiotic concentrations overcomes the need to predict concentrations using mathematical models, there are still several hurdles we need to overcome before TDM can be implemented in daily care.
Article review for the Journal Club on behalf of the WG on antimicrobial use provided by Dr. Sofie Dhaese and Prof. Dr. Hendrik Bracht.
1) Gonçalves-Pereira J, Póvoa P (2011) Antibiotics in critically ill patients: a systematic review of the pharmacokinetics of β-lactams. Crit Care 15:R206 . doi: 10.1186/cc10441
2) Dhaese SAM, Farkas A, Colin P, et al (2018) Population pharmacokinetics and evaluation of the predictive performance of pharmacokinetic models in critically ill patients receiving continuous infusion meropenem: a comparison of eight pharmacokinetic models. J Antimicrob Chemother. doi: 10.1093/jac/dky434
3) Wong G, Briscoe S, Adnan S, et al (2013) Protein binding of β-lactam antibiotics in critically ill patients: can we successfully predict unbound concentrations? Antimicrob Agents Chemother 57:6165–70 . doi: 10.1128/AAC.00951-13
4) Wong G, Briscoe S, McWhinney B, et al (2018) 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. doi: 10.1093/jac/dky314