Critical reappraisal of current issues for improving the proper clinical use of the incoming beta-lactam/beta-lactamase inhibitor combinations of tomorrow

Introduction: Although different novel beta-lactam/beta-lactamase inhibitor combinations (BL/BLIc) were recently licensed, resistance occurrence have been reported up to 15% of Gram-negative pathogens. For this reason, novel BL/BLIc of tomorrow will be released for managing difficult-to-treat resistance (DTR) Gram-negative infections. Areas covered: This review provides a critical reappraisal of current issues for improving the proper clinical use of the novel BL/BLIc of tomorrow. A literature search was performed on PubMed-MEDLINE (until December 2024) for retrieving available studies on cefepime-enmetazobactam, sulbactam-durlobactam, and cefepime-taniborbactam. Four different main areas were discussed according to available evidence: 1) translating findings coming from the randomized clinical trials into the real-world clinical practice; 2) defining the optimal joint pharmacokinetic/pharmacodynamic (PK/PD) target; 3) identifying proper dosing schedules in patients with renal dysfunction; 4) attributing proper relevance to the epithelial lining fluid (ELF) penetration rate in defining optimal dosing schedule for treating pneumonia. Expert opinion: Overall, old habits die hard and issues retrieved with licensed beta-lactams emerged also with novel BL/BLIc of tomorrow, potentially affecting their efficacy when used in real-world practice. Adopting appropriate corrective measures for overcoming these issues might increase the likelihood of preserving their efficacy in the future by minimizing the propensity risk of resistance development.