Pre-Target Interception Defines Carbapenem Failure in Carbapenem-Resistant Enterobacterales: A Mechanistic Framework for Spatiotemporal Drug Reprogramming.

Carbapenem-resistant Enterobacterales (CRE) are a major therapeutic challenge because of limited treatment options and high mortality. Despite advances in resistance-targeted therapies and pharmacokinetic (PK) optimization, treatment failure remains common. This review examines how resistance mechanisms and antibiotic exposure at the infection site jointly influence therapeutic outcomes in CRE infections. A mechanistic synthesis of evidence on carbapenem PKs, bacterial resistance, and nanoparticle (NP)-based delivery systems was performed. Based on this analysis, we propose the Pre-Target Interception Model (PTIM), which describes treatment failure as the progressive loss of active antibiotic before reaching penicillin-binding proteins. Unlike conventional approaches that focus primarily on resistance determinants or drug delivery platforms, PTIM emphasizes the factors that limit effective antibiotic exposure within infected tissues. Within this framework, nanocarrier systems are assessed according to their ability to protect antibiotics, enhance tissue penetration, and improve retention under conditions of enzymatic degradation, membrane restriction, efflux activity, and biofilm-associated diffusion barriers. However, clinical translation remains limited by manufacturing challenges, variability in NP performance, and the lack of validation in CRE-specific settings. Future progress will require quantitative measurement of antibiotic exposure at infection sites, standardized evaluation of nanocarrier performance, and validation in clinically relevant models. PTIM provides a framework for the rational development of nanomedicines designed to improve antibiotic delivery in CRE infections.