Inoculum-dependent activity of contemporary β-lactam agents against carbapenemase- producing Enterobacterales

Carbapenemase-producing Enterobacterales (CPE) pose a major therapeutic challenge because antimicrobial susceptibility measured at standard inoculum may not reflect activity at higher bacterial burdens. This Mini Review examines the biological basis, carbapenemase dependence, and agent-specific expression of inoculum effects among contemporary β-lactams. Increasing bacterial density can enhance β-lactamase burden and extracellular carbapenemase activity, alter the effective drug-to-enzyme relationship, and interact with permeability defects, bacterial physiology, and antimicrobial exposure. Available evidence shows substantial heterogeneity across carbapenemases and agents. Ceftazidime-avibactam appears comparatively stable in several CPE studies, whereas cefiderocol, aztreonam-avibactam, and other β-lactam/β-lactamase inhibitor combinations can show marked density-dependent reductions in activity under specific conditions. However, in vitro MIC increases do not consistently translate into reduced in vivo efficacy. Standardized testing approaches, mechanism-informed susceptibility assessment, and clinically relevant pharmacokinetic and pharmacodynamic studies are needed to clarify the therapeutic significance of inoculum-dependent β-lactam activity.