Pharmacological approaches to overcome antimicrobial resistance to novel beta-lactams in MDR Gram-negative bacterial infections: Current practice and future directions

Introduction: The growing spread of resistance development among Gram-negative pathogens currently represents a worrisome issue for public health. Adopting proper corrective actions aimed at increasing the likelihood of preserving the efficacy of these novel agents by minimizing the propensity risk of resistance development is a compelling need for overcoming this issue. Areas covered: This review provides an updated critical reappraisal focused on preclinical and clinical evidence supporting the usefulness of an aggressive beta-lactams pharmacokinetic/pharmacodynamic (PK/PD) target for overcoming resistance occurrence in Gram-negative infections. A literature search was carried out on PubMed-MEDLINE from January 2015 to December 2025. Expert opinion: Identifying proper strategies allowing to minimize the risk of resistance emergence among Gram-negative pathogens represents a compelling unmet clinical need. From a pharmacological perspective, optimizing the use of novel beta-lactams and beta-lactam/beta-lactamase inhibitor combinations based on PK/PD principles may represent a valuable approach for overcoming antimicrobial resistance. Both preclinical and clinical evidence suggested that attaining an aggressive PK/PD target may allow to prevent resistance emergence to beta-lactams. Delivering beta-lactams by prolonged or continuous infusion and optimizing plasma exposure by means of a therapeutic drug monitoring-guided approach could be helpful tools for maximizing the likelihood of attaining aggressive PK/PD targets with beta-lactams.