Over the past decade, the antimicrobial pipeline has produced several new agents targeting multidrug-resistant Gram-negative pathogens; however, their impact has been limited by the rapid emergence of resistance and heterogeneous activity across resistance mechanisms. Metallo-β-lactamase-producing Enterobacterales and highly resistant Pseudomonas aeruginosa remain challenging targets. Parallel strategies, including microbiome modulation, bacteriophage therapy, and immunotherapeutic approaches, are under investigation and may complement antibiotic therapy, although robust clinical evidence is still evolving. RCT conducted to date have provided important insights but remain limited in their ability to inform optimal clinical management. These studies are typically small, heterogeneous, and primarily designed to support regulatory approval rather than to define treatment strategies for critical ill patients. Consequently, individuals with true “no-option” DTR infections are underrepresented, and the applicability of trial findings to real-world clinical decision-making remains constrained. Guideline development reflects these limitations, with recent recommendations incorporating new antimicrobial agents but often lacking prioritisation and adaptability to local epidemiology, diagnostic capacity, and antimicrobial availability. This has contributed to variability in implementation across regions and highlights the need for more dynamic, evidence-linked clinical algorithms. The presentation will discuss the need to fundamentally rethink clinical trial design. Traditional RCT are poorly suited to the complexity and heterogeneity of DTR infections. Adaptive platform trials offer a more efficient and ethically robust alternative. These designs allow multiple interventions to be evaluated simultaneously and support the continuous evolution of treatment strategies based on accumulating data. Successful advancement in this field will depend on improved data harmonisation, integration of real-world evidence, and the development of perpetual cohort-based platforms. Ultimately, addressing DTR Gram-negative infections requires not only new therapeutics but also a transformation in how clinical evidence is generated, moving from drug-centred evaluation to patient-centred optimisation of treatment strategies in highly vulnerable populations.