DYNAMIC ASSESSMENT OF CEFEPIME/ENMETAZOBACTAM CONCENTRATIONS IN MEDULLA SPINALIS, THE SUBARACHNOID AND EPIDURAL SPACE: AN EXPERIMENTAL PORCINE STUDY

Background Central nervous system (CNS) infections caused by ESBL-producing Enterobacterales are associated with high morbidity and risk of therapeutic failure. While several newer β-lactam/β-lactamase inhibitor combinations have shown encouraging activity against gram-negative CNS infections, pharmacokinetic data for cefepime/enmetazobactam from the CNS have not previously been described. Methods Microdialysis was employed to quantify the unbound concentrations of cefepime and enmetazobactam following intravenous administration. Microdialysis catheters were placed in three CNS compartments: The medulla spinalis, the subarachnoid space, and the epidural space. Sixteen pigs were randomised to receive either a short-term infusion of cefepime/enmetazobactam (2 g/0.5 g over 2 h) or continuous infusion (initial dosage of 1 g/0.5 g administered over 15 min followed by 1 g/0.25 g over 7 h and 45 min) during three 8 h dosing intervals. Microdialysis and plasma samples were collected during the first (0-8 h) and third (16-24 h) dosing interval and quantified by LC–MS/MS. Pharmacokinetic target attainment was evaluated as the percentage of the dosing interval during which concentrations exceeded clinically relevant pharmacokinetic targets for Enterobacterales; 4 mg/L for Cefepime (T>MIC4) and 2 mg/L for enmetazobactam (T>Cthreshold2). Results All pigs completed the study, and data from 44/48 catheters were collected. For cefepime: In all compartments, regardless of administration, the mean T>MIC4 ranged from 98-100% and 97-100% for the first and third dosing interval, respectively. For enmetazobactam: In the first dosing interval, the mean T>Cthreshold2 ranged from 82-99% (short-term infusion) and 96-100% (continuous infusion) across all compartments. In the third dosing interval, the mean T>Cthreshold2 ranged from 85-100% (short-term infusion), and from 89-100% (continuous infusion) across all compartments. Conclusions This study presents the first dynamic pharmacokinetic data on cefepime/enmetazobactam penetration into the CNS. High T>MIC and T>Cthreshold target attainments were achieved in the medulla spinalis, the subarachnoid space and the epidural space, irrespective of mode of administration. These novel findings offer a quantitative foundation for optimising dosing strategies for cefepime/enmetazobactam in the management of CNS infections caused by ESBL-producing Enterobacterales.