Serum and peritoneal exudate concentrations after high doses of β-lactams in critically ill patients with severe intra-abdominal infections: an observational prospective study.

Background: Critically ILL patients with severe intra-abdominal infections (IAIs) requiring surgery may undergo several pharmacokinetic (PK) alterations that can Lead to beta-Lactam underdosage. Objectives: To measure serum and peritoneal exudate concentrations of beta-Lactams after high doses and optimal administration schemes. Methods: This observational prospective study included critically ILL patients with suspicion of IAI who required surgery and a beta-Lactam antibiotic as empirical therapy. Serum and peritoneal exudate concentrations were measured during surgery and after a 24h steady-state period. The PK/pharmacodynamic (PD) target was to obtain serum beta-Lactam concentrations of 100% fT(>4xMIC) based on a worst-case scenario (based on the EUCAST highest epidemiological cut-off values) before bacterial documentation (a priori) and redefined following determination of the MIC for the isolated bacteria (a posteriori). Registered with ClinicalTrials.gov (NCT03310606). Results: Forty-eight patients were included with a median (IQR) age of 64 (53-74) years and a SAPS II of 40 (32-65). The main diagnosis was secondary nosocomial peritonitis. Piperacillin/tazobactam was the most administered beta-Lactam antibiotic (75%). The serum/peritoneal piperacillin/tazobactam ratio was 0.88 (0.64-0.97) after a 24 h steady-state period. Prior to bacterial documentation, 16 patients (33.3%) achieved the a priori PK/PD target. The identification of microorganisms was available for 34 patients (71%). Based on the MIC for isolated bacteria, 78% of the patients achieved the serum PK/PD target. Conclusions: In severe IAIs, high doses of beta-Lactams ensured 100% fT(>4xMIC) in the serum for 78% of critically ILL patients with severe IAIs within the first 24 h. In order to define optimal beta-Lactam dosing, the PK/PD target should take into account the tissue penetration and Local ecology.