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

ABSTRACT

BACKGROUND: Critically ill patients with severe intra-abdominal infections (IAIs) requiring surgery may undergo several pharmacokinetic (PK) alterations that can lead to ß-lactam underdosage. OBJECTIVES: To measure serum and peritoneal exudate concentrations of ß-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 ß-lactam antibiotic as empirical therapy. Serum and peritoneal exudate concentrations were measured during surgery and after a 24 h steady-state period. The PK/pharmacodynamic (PD) target was to obtain serum ß-lactam concentrations of 100% fT>4×MIC 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 ß-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 ß-lactams ensured 100% fT>4×MIC in the serum for 78% of critically ill patients with severe IAIs within the first 24 h. In order to define optimal ß-lactam dosing, the PK/PD target should take into account the tissue penetration and local ecology.