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Antimicrob Agents Chemother. 2019 Jan 2. pii: AAC.02134-18. doi: 10.1128/AAC.02134-18. [Epub ahead of print]

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

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Pharmacy and Clinical Pharmacy Department, CHU Bordeaux, 33000 Bordeaux, France.
Anesthesiology and Critical Care Department, CHU Bordeaux, 33000 Bordeaux, France
Pharmacokinetics and PK/PD Group INSERM 1034, Univ. Bordeaux, 33000 Bordeaux, France.
Anesthesiology and Critical Care Department, CHU Bordeaux, 33000 Bordeaux, France.
Univ. Bordeaux Segalen, 33000 Bordeaux, France.


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 (ClCrL) measurements and therapeutic drug monitoring of unbound ceftriaxone. ARC was defined by a ClCr ≥ 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 ClCr (<150, 150 to 200 and >200 ml/min).Results: Twenty-one patients were included. The rate of empirical ceftriaxone underdosing was 62% (39/63). ClCr ≥ 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. ClCr 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 ClCr ≥ 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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