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Aggressive pharmacokinetic (PK)/pharmacodynamic (PD) targets have shown better microbiological eradication rates and a lower propensity to develop resistant strains than conservative targets. We investigated whether meropenem blood levels, including aggressive PK/PD, were acceptable in terms of efficacy and safety using a meropenem regimen of 1 g infusion every 8 h over 3 h in patients undergoing continuous renal replacement therapy (CRRT) for septic acute kidney injury (AKI). Aggressive PK/PD targets were defined as the percentage of time that the free concentration (%fT) > 4 × minimal inhibitory concentration (MIC), the toxicity threshold was defined as a trough concentration >45 mg/L, and the percentage of achievement at each MIC was evaluated. The 100% fT > 4 × MIC for a pathogen with an MIC of 0.5 mg/L was 89%, and that for a pathogen with an MIC of 2 mg/L was 56%. The mean steady-state trough concentration of meropenem was 11.9 ± 9.0 mg/L and the maximum steady-state trough concentration was 29.2 mg/L. Simulations using Bayesian estimation showed the probability of achieving 100% fT > 4 × MIC for up to an MIC of 2 mg/L for the administered administration via continuous infusion at 3 g/24 h. We found that an aggressive PK/PD could be achieved up to an MIC of 0.5 mg/L with a meropenem regimen of 1 g infused every 8 h over 3 h for patients receiving CRRT for septic AKI. In addition, the risk of reaching the toxicity range with this regimen is low. In addition, if the MIC was 1–2 mg/L, the simulation results indicated that aggressive PK/PD can be achieved by continuous infusion at 3 g/24 h without increasing the daily dose. [ABSTRACT FROM AUTHOR] more...

In Japan, the post-dilution method is preferred to maintain the dialysis efficiency of low molecular weight substances in continuous hemodiafiltration (CHDF). In contrast, the pre-dilution method is preferable to ensure a stable filter lifetime, especially for membranes with cytokine absorptive characteristics that are at high risk of membrane coagulation. However, the impact of the dilution method on the removal performance of adsorptive membranes for cytokines remains unclear. This study aimed to investigate the effect of different dilution methods on the adsorption clearance of cytokine on polymethylmethacrylate (PMMA) membranes by in vitro experiments. Bovine albumin, interleukin (IL)-6, and creatinine were added to phosphate-buffered saline to achieve final concentrations of 3.5 g/dL, 1000 pg/mL, and 10 mg/dL, respectively. The test solution was passed through the 1.8 m 2 PMMA membrane hemofilter at a flow rate of 100 mL/min in a single-pass system. The dialysate/filtration flow rates used were 2.5/2.5, 5.0/5.0, and 7.5/7.5 mL/min for each pre- and post-dilution method. Samples were collected seven times from pre- and post-hemofilter every minute, 10 min after the start of CHDF. Samples were frozen and stored, and the concentration of IL-6 was measured by enzyme-linked immunosorbent assay (ELISA), and clearance was calculated. Creatinine clearance increased with an increasing flow rate in pre- and post-dilution, while IL-6 clearance was less affected by flow rate. IL-6 clearance was 35.5 mL/min (32.1-39.6) for pre-dilution and 37.1 mL/min (33.8-41.1) for post-dilution in the 2.5/2.5 setting, and 34.2 mL/min (28.8-36.2) for pre-dilution and 32.4 mL/min (32.4-37.4) for post-dilution in the 5.0/5.0 setting. The dilution methods showed no significant differences. Moreover, in the 7.5/7.5 setting, clearance was 29.5 mL/min (27.7-37.2) for pre-dilution and 39.9 mL/min (37.8-41.5) for post-dilution (P<0.001); however, all clearance values were higher than theoretical values expected from filtration removal. In conclusion, the cytokine removal characteristics of the PMMA membrane hemofilter were not largely affected by the dilution method, and IL-6 clearance could be fully demonstrated even in the pre-dilution method., Competing Interests: Human subjects: All authors have confirmed that this study did not involve human participants or tissue. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: Yoshiki Masuda received lecture fees from MSD K.K., Japan Blood Products Organization, and Asahi Kasei Corporation and an industry-academia collaborative research grant from JIMRO Co., Ltd. Mototsugu Kudo received collaborative research grant from Toray Co., Ltd. Hiroomi Tatsumi received lecture fees from Otsuka Pharmaceutical Factory, Inc. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2025, Kudo et al.) more...