Resistome Flux in the Environment: A 3Es and 3Ds Perspective with emphasis on Wastewater-Human Nexus

• The environment plays a dual role in both driving the spread and enabling the containment of AMR • Persistence of AMR in the environment is influenced by fitness costs and selective pressures • Environmental transmission pathways allow for the acquisition of resistance by non-resistant bacterial strains, exacerbating the problem. • Environmental AMR surveillance provides valuable epidemiological insights and is crucial for implementing the One Health approach. • Effective AMR monitoring requires strategic sampling design and advanced detection methods, including culture-based, molecular, and bioinformatic tools • Integrated monitoring frameworks are essential for guiding evidence-based policies and sustainable AMR interventions at the environmental, human, and animal health interface. Antimicrobial resistance is an escalating global health challenge that transcends clinical boundaries, rooted in complex interactions among antimicrobials, microbial ecosystems, and human activity. This review applies a systems-oriented framework that integrates the 3Es (Evolution, Exposure, Epidemiology) with the 3Ds (Drivers, Dissemination, Detection) to evaluate resistome flux in the environment, with a particular emphasis on wastewater. By synthesizing evidence across water, soil, and air pathways, we highlight how resistance genes emerge, persist, and disseminate, shaped by mobile genetic elements, co-selective pressures, and anthropogenic drivers. Current studies, while extensive, remain largely descriptive and provide limited connections to clinical outcomes, underscoring the need for approaches that couple ecological and genomic insights with health-relevant risk assessments. WBE is a promising surveillance platform, yet faces challenges including marker instability, contributions from non-human sources, and difficulties in data interpretation. Improving reliability requires genotypic AMR detection, composite and longitudinal sampling, and concurrent integration with clinical datasets. Standardizing WBE protocols globally, together with ARG risk-ranking frameworks (e.g., SARG), will enhance comparability and translational value. A watchlist of emerging ARGs including latent and proto-ARGs, could further guide surveillance priorities and diagnostic development. Cross-sectoral collaboration, transparent data sharing, and digital tools such as GIS-linked dashboards are essential for identifying AMR hotspots, guiding interventions, and informing policy. By integrating 3Es/3Ds with WBE, this review provides a roadmap for long-term monitoring, functional validation of ARG mobility, and actionable strategies to mitigate AMR at both community and global scales.