Reimagining Antimicrobial Drug Delivery: Spatiotemporally Adaptive Therapeutics for Biofilm-Associated Infections and Antimicrobial Resistance.

Antimicrobial therapy may fail even when an agent is intrinsically active if effective drug exposure is not achieved at the site of infection at the appropriate time. This challenge is particularly important in biofilm-associated infections and infections caused by drug-resistant pathogens, where biological barriers, spatial heterogeneity, and changing microbial states can limit treatment effectiveness. This narrative review examines advanced antimicrobial delivery from a problem-oriented perspective, focusing on the therapeutic challenges that delivery systems are designed to address. It explores how antimicrobial exposure can be aligned with the location, biological state, and changing course of infection. The review examines the biological and pharmacological barriers that restrict antimicrobial activity and discusses strategies designed to improve drug access, retention, release, and local activity. Localized delivery, responsive and externally triggered systems, controlled and sequential delivery, and multimodal therapy are considered as implementation strategies within a common spatiotemporal framework. Particular attention is given to the relationship between formulation design, local drug exposure, biological response, and therapeutic outcome. The review further examines the factors that determine whether a technically promising system has a realistic clinical role, including safety, reproducibility, manufacturability, model relevance, and demonstrable benefits over simpler approaches. Future priorities are considered from a clinically defined perspective. Overall, the review argues that the value of advanced antimicrobial delivery lies not in carrier complexity alone, but in its capacity to provide a measurable and reproducible therapeutic advantage for a clearly defined infection setting.