Population pharmacokinetics of ceftriaxone administered as continuous or intermittent infusion in critically ill patients

Abstract

Objectives To describe the population pharmacokinetics and protein-binding characteristics of unbound ceftriaxone administered as continuous or intermittent infusion. Additionally, to determine the optimal dosing regimen in critically ill patients. Methods A pharmacokinetic study was performed in the ICU of a tertiary teaching hospital. Patients were treated with ceftriaxone as continuous or intermittent infusion. A population pharmacokinetic model was developed with non-linear mixed-effects analysis. Subsequently, the PTA of a 100% T>MIC was assessed for influential patient characteristics using Monte Carlo simulation. Results Fifty-five patients were included. The pharmacokinetics of ceftriaxone was best described by a one-compartment model with non-linear saturable protein binding including the following covariates: body weight, estimated CLCR, serum albumin concentration and mode of administration. For pathogens with an MIC of 1 mg/L, the simulation demonstrated that intermittent infusion of 2 g/24 h only resulted in a ≥90% PTA in patients with a reduced CLCR (0–60 mL/min). Intermittent infusion of 2 g/12 h led to sufficient exposure if CLCR was 0–90 mL/min and continuous infusion of 2 g/24 h led to a ≥90% PTA in all simulations (CLCR 0–180 mL/min). Conclusions In the critically ill, the clearance of unbound ceftriaxone is closely related to CLCR. Furthermore, ceftriaxone protein binding is saturable, variable and dependent on serum albumin concentration. Intermittent dosing of 2 g/24 h ceftriaxone leads to subtherapeutic exposure in patients with a normal or increased CLCR. Treating these patients with continuous infusion of 2 g/24 h is more effective than an intermittent dosing regimen of 2 g/12 h.

Pharmacokinetic/Pharmacodynamic Target Attainment Based on Measured versus Predicted Unbound Ceftriaxone Concentrations in Critically Ill Patients with Pneumonia: An Observational Cohort Study

“…In accordance with previous PK studies in septic [ 9 ], general ICU [ 10 , 11 , 12 ] or non-ICU [ 18 ] patients, PK/PD target attainment was suboptimal for ceftriaxone 2 g q24h in patients with severe CAP. Interestingly, despite the relatively high age in our study population, renal function was still well preserved.…”

“…Next to meropenem and piperacillin, ceftriaxone is one of the most frequently monitored β-lactams in the ICU [ 8 ]. Studies have shown suboptimal PK/PD target attainment in septic [ 9 ] or general ICU [ 10 , 11 , 12 ] patients treated with ceftriaxone. Nevertheless, routine TDM for ceftriaxone has still not found its way into clinical practice [ 7 , 13 ].…”

“…In the ICU setting, where hypoalbuminemia is present in up to 50% of all patients, the unbound ceftriaxone fraction is highly variable [ 15 , 16 , 17 ]. This is probably due to its nonlinear concentration-dependent protein binding [ 10 , 18 ]. Measuring the unbound fraction using equilibrium dialysis, which is the reference method, is time-consuming and costly [ 19 , 20 ].…”

Therapeutic Drug Monitoring of Meropenem and Piperacillin in Critical Illness—Experience and Recommendations from One Year in Routine Clinical Practice

“…We thought that the chosen high breakpoints for target attainment were necessary due to the high number of immunocompromised patients who underwent lung or liver transplantation and had special pathogens with higher MICs than other patients [31,32]. The number of subtherapeutic levels was comparable to those reported in the literature for meropenem [17,33,34], piperacillin [7,35,36], and other beta-lactam antibiotics like cefepime [37] or ceftriaxone [38]. Furthermore, the existing correlation between renal function and beta-lactam blood concentration has also been described in different studies [21,22].…”

What Are the Current Approaches to Optimising Antimicrobial Dosing in the Intensive Care Unit?

“… Exclusion—RRT, life expectancy < 12 h. Model covariates—adjusted body weight, plasma albumin concentration, creatinine clearance (Cockcroft-Gault), method of administration (continuous infusion or intermittent bolus). Garot D et al [ 126 ] Leegwater E et al [ 127 ] [ 126 , 127 ] Ciprofloxacin Adult ICU. N = 102 patients (588 plasma samples).…”