Are standard dosing regimens of ceftriaxone adapted for critically ill patients with augmented creatinine clearance? A prospective observational study. [Pharmacology]

Objective: To determine whether augmented renal clearance (ARC) impacts negatively on ceftriaxone pharmacokinetic/pharmacodynamics (PK/PD) target attainment in critically ill patients.

Methods: Over a 9-month period, all critically ill patients treated by ceftriaxone were eligible. During the first three days of antimicrobial therapy, every patient underwent 24-hour creatinine clearance (Cl_CrL) measurements and therapeutic drug monitoring of unbound ceftriaxone. ARC was defined by a Cl_Cr ≥ 150 ml/min. Empirical underdosing was defined by a trough unbound ceftriaxone concentration under 2 mg/L (100%fT_>MIC). Monte Carlo simulation (MCS) was performed to determine the probability of target attainment (PTA) of different dosing regimen for various MIC and three groups of Cl_Cr (<150, 150 to 200 and >200 ml/min).

Results: Twenty-one patients were included. The rate of empirical ceftriaxone underdosing was 62% (39/63). Cl_Cr ≥ 150 ml/min was associated with empirical target underdosing with an OR = 8.8 [2.5 – 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 MCS, the proportion of patients who would failed to achieve 100%fT>MIC was significantly higher in ARC patients for each dosage regimen (OR = 2.96 [2.74; 3.19], p < 0.01). A dose of 2g twice a day was best suited to achieve a 100%fT_>MIC.

Conclusion: When targeting 100%fT_>MIC of the less susceptible pathogens, patients with Cl_Cr ≥ 150 ml/min remain at risk of empirical ceftriaxone underdosing. These data emphasize the need of therapeutic drug monitoring in ARC patients.

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