Abstract
IntroductionAltered 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.MethodsOpen, 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.Results80 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.ConclusionsSerum 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.
Highlights
Altered pharmacokinetics (PK) in critically ill patients can result in insufficient serum β-lactam concentrations when standard dosages are administered
As there is a large variance in minimal inhibitory concentration (MIC) values for different bacteria, we considered the MICs for problematic pathogens, such as P. aeruginosa, commonly isolated in ICU patients, as the empiric target threshold [25]
In this study, we show that current standard first doses of piperacillin-tazobactam, cefepime and ceftazidime are insufficient to maintain therapeutic serum concentrations greater than four times the MIC of P. aeruginosa in patients with severe sepsis and septic shock
Summary
Altered pharmacokinetics (PK) in critically ill patients can result in insufficient serum β-lactam concentrations when standard dosages are administered. Antibiotherapy in critically ill septic patients usually consists of a broad-spectrum β-lactam combined with a glycopeptide and/or an aminoglycoside [5] These drugs regimens, serum β-lactam concentrations may fall to low levels between doses [11,12], with potentially negative effects on clinical response and emergence of resistances. As previous PK studies on β-lactams in ICU patients have excluded the most severely ill patients or were conducted in the steady-state period of treatment [15,16,17], the main objective of this study was to determine whether the currently recommended first dose of four broad-spectrum β-lactams (piperacillin-tazobactam, ceftazidime, cefepime, and meropenem) provide adequate plasma concentrations in critically ill septic patients in the ICU. We tried to determine whether clinical or hemodynamic parameters could affect the PK profile of these drugs during such severe infections
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
