Insufficient β-lactam concentrations in the early phase of severe sepsis and septic shock.
BACKGROUND
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.
Taccone
Fabio Silvio
FS
Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles, route de Lennik 808, 1070 Bruxelles, Belgium. ftaccone@ulb.ac.be
Laterre
Pierre-François
PF
Dugernier
Thierry
T
Spapen
Herbert
H
Delattre
Isabelle
I
Wittebole
Xavier
X
De Backer
Daniel
D
Layeux
Brice
B
Wallemacq
Pierre
P
Vincent
Jean-Louis
JL
Jacobs
Frédérique
F
D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000077723:Cefepime; D002442:Ceftazidime / Q000097:blood / Q000627:therapeutic use; D002511:Cephalosporins / Q000097:blood / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D010397:Penicillanic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000627:therapeutic use; D010878:Piperacillin / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use; D011446:Prospective Studies; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism; D012772:Shock, Septic / Q000188:drug therapy* / Q000378:metabolism; D000078142:Tazobactam; D013845:Thienamycins / Q000097:blood / Q000627:therapeutic use; D047090:beta-Lactams / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D013845:Thienamycins; D047090:beta-Lactams; D000077723:Cefepime; D010397:Penicillanic Acid; D002442:Ceftazidime; D000077731:Meropenem; D000078142:Tazobactam; D010878:Piperacillin