Insufficient β-lactam concentrations in the early phase of severe sepsis and septic shock

Fabio Silvio Taccone, Pierre-François Laterre, Thierry Dugernier, Herbert Spapen, Isabelle Delattre, Xavier Wittebole, Daniel De Backer, Brice Layeux, Pierre Wallemacq, Jean-Louis Vincent, Frédérique Jacobs, Fabio Silvio Taccone, Pierre-François Laterre, Thierry Dugernier, Herbert Spapen, Isabelle Delattre, Xavier Wittebole, Daniel De Backer, Brice Layeux, Pierre Wallemacq, Jean-Louis Vincent, Frédérique Jacobs

Abstract

Introduction: Altered pharmacokinetics (PK) in critically ill patients can result in insufficient serum β-lactam concentrations when standard dosages are administered. Previous studies on β-lactam PK have generally excluded the most severely ill patients, or were conducted during the steady-state period of treatment. The aim of our study was to determine whether the first dose of piperacillin-tazobactam, ceftazidime, cefepime, and meropenem would result in adequate serum drug concentrations in patients with severe sepsis and septic shock.

Methods: Open, prospective, multicenter study in four Belgian intensive care units. All consecutive patients with a diagnosis of severe sepsis or septic shock, in whom treatment with the study drugs was indicated, were included. Serum concentrations of the antibiotics were determined by high-pressure liquid chromatography (HPLC) before and 1, 1.5, 4.5 and 6 or 8 hours after administration.

Results: 80 patients were treated with piperacillin-tazobactam (n = 27), ceftazidime (n = 18), cefepime (n = 19) or meropenem (n = 16). Serum concentrations remained above 4 times the minimal inhibitory concentration (T > 4 × MIC), corresponding to the clinical breakpoint for Pseudomonas aeruginosa defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), for 57% of the dosage interval for meropenem (target MIC = 8 μg/mL), 45% for ceftazidime (MIC = 32 μg/mL), 34% for cefepime (MIC = 32 μg/mL), and 33% for piperacillin-tazobactam (MIC = 64 μg/mL). The number of patients who attained the target PK profile was 12/16 for meropenem (75%), 5/18 for ceftazidime (28%), 3/19 (16%) for cefepime, and 12/27 (44%) for piperacillin-tazobactam.

Conclusions: Serum concentrations of the antibiotic after the first dose were acceptable only for meropenem. Standard dosage regimens for piperacillin-tazobactam, ceftazidime and cefepime may, therefore, be insufficient to empirically cover less susceptible pathogens in the early phase of severe sepsis and septic shock.

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