β-Lactam/β-Lactamase Inhibitor Combinations in Sepsis-Associated Acute Kidney Injury and Renal Replacement Therapy

Area of Science:

• Pharmacology and Nephrology
• Antimicrobial Stewardship
• Critical Care Medicine

Background:

• Sepsis-associated acute kidney injury (SA-AKI) frequently necessitates renal replacement therapy (RRT).
• RRT significantly impacts antimicrobial pharmacokinetics (PK) and pharmacodynamics (PD), complicating treatment.
• Novel beta-lactam/beta-lactamase inhibitor (BL/BLI) combinations offer expanded options against multidrug-resistant Gram-negative bacteria, but their dosing during RRT is not well-established.

Purpose of the Study:

• To review the PK/PD characteristics, extracorporeal clearance, and dosing considerations of key BL/BLI agents in patients with SA-AKI undergoing RRT.
• To highlight the variability in drug exposure based on RRT modality and patient-specific factors.
• To provide practical guidance for optimizing BL/BLI use in this complex patient population.

Main Methods:

• Systematic review of experimental models, case reports, and clinical studies.
• Extraction and synthesis of data on PK/PD, RRT impact, PK/PD targets, pediatric considerations, and clinical outcomes for various BL/BLI agents.
• Analysis of factors influencing drug exposure, including RRT settings and patient characteristics (e.g., augmented renal clearance, hypoalbuminemia, fluid overload).

Main Results:

• Drug exposure to BL/BLIs varies significantly with RRT modality, effluent flow, membrane properties, and patient factors.
• Standard renal-adjusted dosing frequently results in subtherapeutic drug concentrations in critically ill patients on RRT.
• Pediatric data are scarce, primarily limited to case reports.

Conclusions:

• Optimal use of BL/BLIs in septic patients with SA-AKI on RRT requires individualized dosing strategies that account for PK/PD variability and dialysis parameters.
• Initiating full doses within the first 24-48 hours, followed by careful adjustments, is a prudent approach.
• Therapeutic drug monitoring and institution-specific protocols integrated into stewardship programs are recommended to enhance efficacy and combat resistance.