Defining Exposure Predictors of Meropenem That Are Associated with Improved Survival for Severe Bacterial Infection: A Preclinical PK/PD Study in Sepsis Rat Model

Background: The pharmacokinetic/pharmacodynamic (PK/PD) index of carbapenems that best correlates with in vivo antimicrobial activity is percent time of dosing interval in which free drug concentration remains above MIC (%fT > MIC), while the magnitudes of the PK/PD index of carbapenems remains undefined in critically ill sepsis patients. Methods: A sepsis rat model was first developed by comparing the survival outcomes after intraperitoneal injection of different inoculum size (1–10 × 107 CFU) of Pseudomonas aeruginosa ATCC9027 (MIC = 0.125 mg/L) in neutropenic rats. The PK characteristics of the model drug meropenem in the developed sepsis rat model was then evaluated, and PK modeling and simulation was applied to design meropenem dosing regimens attaining various PD targets (40%fT > MIC, 100%fT > MIC, and 100%fT > 4 × MIC). The microbiological response and survival outcomes for different meropenem treatment regimens were investigated in the rat sepsis model (n = 12 for each group). Results: The optimal inoculum for the rat sepsis model was 1 × 107 CFU of Pseudomonas aeruginosa ATCC9027. A one-compartment model with first-order absorption best described the PK of meropenem in sepsis rats. Pronounced survival prolongation and lower hazard risk were observed in the treatment groups of 50 or 75 mg/kg/q2.4h (100%fT > MIC) and 75 mg/kg/q2h (100%fT > 4 × MIC) compared to the 75 mg/kg/q6h (40%fT > MIC) group, while meropenem groups with PD targets of 100%fT > MIC and 100%fT > 4 × MIC showed comparable survival curves. Microbiological response for different PD targets is inconclusive due to irregular bacterial counts in blood samples. Conclusions: The PD target of 40%fT > MIC is suboptimal for sepsis rats, and the aggressive 100%fT > 4 × MIC target does not provide a survival benefit against the target of 100%fT > MIC