Real-World Evidence and Multidrug Resistant Infections: How Can We Leverage RWE to Improve Patient Outcome with the Novel Beta-Lactam and Beta-Lactam/Beta-Lactamase Inhibitor Combinations

Translating findings emerged from pivotal trials of novel beta-lactams into real-world clinical practice represents a major concern. Real-world evidence assessing the efficacy of novel beta-lactams in different clinical scenarios may provide some benefits in selecting proper place in therapy. This review aims to perform a critical reappraisal of the issues emerged from pivotal trials of novel beta-lactams and leveraging real-world evidence supporting proper place in therapy in the treatment of multidrug-resistant Gram-negative infections. A comprehensive literature search was performed on PubMed-MEDLINE from January 2015 to September 2025 for identifying pivotal trials and real-world evidence concerning the use of cefiderocol and of novel beta-lactam/beta-lactamase inhibitor combination (BL/BLIc) including those of tomorrow (ie, ceftolozane-tazobactam, ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, cefepime-enmetazobactam, cefepime-taniborbactam, cefepime-zidebactam, sulbactam-durlobactam, aztreonam-avibactam). Critical issues emerged from pivotal trials in terms of potential appropriate place in therapy of each included agent were summarized. Four different therapeutic algorithms were proposed according to the pattern of antibiotic susceptibility of the pathogens, the genotype of resistance, and pharmacokinetic/pharmacodynamic (PK/PD) features of selected agents: a) extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales; b) carbapenem-producing Enterobacterales (CPE); c) metallo-beta-lactamase (MBL)-producing Pseudomonas aeruginosa; d) carbapenem-resistant Acinetobacter baumannii (CRAB). Real-world evidence suggested that cefepime-enmetazobactam may represent an effective carbapenem-sparing strategy in the management of infections caused by ESBL-producing Enterobacterales and a potential alternative to ceftazidime-avibactam for treating OXA-48-producing infections. Cefepime-taniborbactam, cefepime-zidebactam, and aztreonam-avibactam could finally represent a definitive answer in the challenging scenario of infections caused by MBL-producing Enterobacterales and Pseudomonas aeruginosa. Lastly, the valuable role of sulbactam-durlobactam in CRAB infections was already recognized by international guidelines. Real-world evidence concerning both well-designed observational studies and PK/PD models may represent a mandatory tool for overcoming issues associated with pivotal trials evaluating novel BL/BLIc. The implementation of dedicated well-designed real-world studies would be warranted for ensuring a constant update of proposed therapeutic algorithms