Abstract
The objective of the present study was to determine whether augmented renal clearance (ARC) impacts negatively on ceftriaxone pharmacokinetic (PK)/pharmacodynamic (PD) target attainment in critically ill patients. Over a 9-month period, all critically ill patients treated with ceftriaxone were eligible. During the first 3 days of antimicrobial therapy, every patient underwent 24-h creatinine clearance (CL(CR)) measurements and therapeutic drug monitoring of unbound ceftriaxone. ARC was defined by a CL(CR) of ≥150 ml/min. Empirical underdosing was defined by a trough unbound ceftriaxone concentration under 2 mg/liter (percentage of the time that the concentration of the free fraction of drug remained greater than the MIC [fT(>MIC)], 100%). Monte Carlo simulation (MCS) was performed to determine the probability of target attainment (PTA) of different dosing regimens for various MICs and three groups of CL(CR) (<150, 150 to 200, and >200 ml/min). Twenty-one patients were included. The rate of empirical ceftriaxone underdosing was 62% (39/63). A CL(CR) of ≥150 ml/min was associated with empirical target underdosing with an odds ratio (OR) of 8.8 (95% confidence interval [CI] = 2.5 to 30.7; P < 0.01). Ceftriaxone PK concentrations were best described by a two-compartment model. CL(CR) was associated with unbound ceftriaxone clearance (P = 0.02). In the MCS, the proportion of patients who would have failed to achieve a 100% fT(>MIC) was significantly higher in ARC patients for each dosage regimen (OR = 2.96; 95% CI = 2.74 to 3.19; P < 0.01). A dose of 2 g twice a day was best suited to achieve a 100% fT(>MIC) When targeting a 100% fT(>MIC) for the less susceptible pathogens, patients with a CL(CR) of ≥150 ml/min remained at risk of empirical ceftriaxone underdosing. These data emphasize the need for therapeutic drug monitoring in ARC patients.