Abstract
The impact of ceftriaxone pharmacokinetic alterations on protein binding and PK/PD target attainment still remains unclear. We evaluated pharmacokinetic/pharmacodynamic (PK/PD) target attainment of unbound ceftriaxone in critically ill patients with severe community-acquired pneumonia (CAP). Besides, we evaluated the accuracy of predicted vs. measured unbound ceftriaxone concentrations, and its impact on PK/PD target attainment. A prospective observational cohort study was carried out in adult patients admitted to the intensive care unit with severe CAP. Ceftriaxone 2 g q24h intermittent infusion was administered to all patients. Successful PK/PD target attainment was defined as unbound trough concentrations above 1 or 4 mg/L throughout the whole dosing interval. Acceptable overall PK/PD target attainment was defined as successful target attainment in ≥90% of all dosing intervals. Measured unbound ceftriaxone concentrations (CEFu) were compared to unbound concentrations predicted from various protein binding models. Thirty-one patients were included. The 1 mg/L and 4 mg/L targets were reached in 26/32 (81%) and 15/32 (47%) trough samples, respectively. Increased renal function was associated with the failure to attain both PK/PD targets. Unbound ceftriaxone concentrations predicted by the protein binding model developed in the present study showed acceptable bias and precision and had no major impact on PK/PD target attainment. We showed suboptimal (i.e., <90%) unbound ceftriaxone PK/PD target attainment when using a standard 2 g q24h dosing regimen in critically ill patients with severe CAP. Renal function was the major driver for the failure to attain the predefined targets, in accordance with results found in general and septic ICU patients. Interestingly, CEFu was reliably predicted from CEFt without major impact on clinical decisions regarding PK/PD target attainment. This suggests that, when carefully selecting a protein binding model, CEFu does not need to be measured. As a result, the turn-around time and cost for ceftriaxone quantification can be substantially reduced.
Highlights
Community-acquired pneumonia (CAP) is a major reason for hospital admission [1,2,3].Five to forty percent of the patients hospitalized with a diagnosis of CAP require admission to the intensive care unit (ICU), which is commonly defined as severe CAP [4].Ceftriaxone is a first-line antimicrobial often prescribed for the empirical treatment of severe CAP
We aimed to evaluate if PK/PD target attainment of CEFu measured by equilibrium dialysis was acceptable in patients admitted to the ICU with severe CAP
We showed suboptimal CEFu PK/PD target attainment for standard ceftriaxone 2 g q24h intermittent dosing in critically ill patients with severe CAP
Summary
Community-acquired pneumonia (CAP) is a major reason for hospital admission [1,2,3].Five to forty percent of the patients hospitalized with a diagnosis of CAP require admission to the intensive care unit (ICU), which is commonly defined as severe CAP [4].Ceftriaxone is a first-line antimicrobial often prescribed for the empirical treatment of severe CAP. Five to forty percent of the patients hospitalized with a diagnosis of CAP require admission to the intensive care unit (ICU), which is commonly defined as severe CAP [4]. For β-lactam antibiotics, pharmacokinetic/pharmacodynamic (PK/PD) target attainment, defined as time above the minimal inhibitory concentration (MIC), has been linked to positive clinical outcomes in critically ill patients [6]. As a result of large PK variability in critically ill patients, standard dosing regimens for several β-lactams have been shown to lead to suboptimal PK/PD target attainment [6,7]. Routine TDM for ceftriaxone has still not found its way into clinical practice [7,13] This may be due to the fact that ceftriaxone PK alterations and the impact on protein binding and PK/PD target attainment still remain unclear in specific populations
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
