Imipenem and relebactam pharmacokinetics in peritoneal fluid: microdialysis reveals infection-independent penetration.

Imipenem/relebactam is a promising therapy for complicated intra-abdominal infections caused by carbapenem-resistant Enterobacterales species. However, data on tissue-site pharmacokinetics are limited. We evaluated the peritoneal penetration of imipenem and relebactam in healthy and infected rats by using microdialysis. The animals received a single intravenous infusion of imipenem (45 mg/kg) and relebactam (22.5 mg/kg), and unbound concentrations were dynamically monitored in the plasma and peritoneal fluid. Imipenem exposure in the peritoneal fluid was consistently lower than that in the plasma, with peritoneal fluid-to-plasma AUC ratios of 0.29 in the control group and 0.27 in the infection group. In contrast, relebactam demonstrated nearly equivalent concentrations in both compartments, with ratios of 0.81 and 0.86, respectively. Both agents reached peak levels at 30 min, and the semi-logarithmic curves showed rapid equilibrium without delay. The partition coefficients estimated by two-compartment modeling for imipenem (0.333-0.342) and relebactam (0.679-0.816) were consistent with non-compartmental results. Infection increased the distribution volume and clearance of relebactam but did not significantly alter peritoneal permeability for either drug. These findings provide the first description of the penetration of relebactam into peritoneal fluid. Subsequent pharmacodynamic target attainment (PTA) analysis showed that under the latest EUCAST PK/PD criteria, PTA values dropped markedly to an MIC of 1 mg/L, indicating a substantially reduced probability of achieving adequate peritoneal exposure. These results highlight the need for dosing strategies to ensure sufficient peritoneal drug concentration to maintain antimicrobial efficacy.