Metallo-β-lactamase-producing Pseudomonas aeruginosa: epidemiology, diagnostic challenges and therapeutic strategies in the era of MDR/XDR resistance

Background The management of multidrug-resistant (MDR) Pseudomonas aeruginosa has evolved from an antibiotic-centric approach to a mechanism-driven paradigm. Among resistance determinants, metallo-β-lactamases (MBLs) represent a critical challenge due to their ability to hydrolyse most β-lactams and their increasing global dissemination within high-risk clones. Methods This narrative review aims to summarize the epidemiology, diagnostic approaches and therapeutic strategies for infections caused by MBL-producing P. aeruginosa , emphasizing a mechanism-based clinical framework. A PubMed-MEDLINE search was conducted up to 1 June 2026 using the terms “ Pseudomonas aeruginosa ”, “ carbapenem resistance ”, and “ metallo- β -lactamase ”. Relevant studies were selected based on the authors' assessment of methodological quality and clinical relevance. Results P. aeruginosa exhibits multifactorial resistance involving intrinsic mechanisms (efflux pumps, AmpC overexpression, porin loss), adaptive responses and acquired carbapenemases. MBLs, especially VIM, IMP, and emerging NDM variants, are increasingly associated with carbapenem resistance and epidemic high-risk clones (e.g., ST235, ST111). Global epidemiology shows marked geographic variability in prevalence and molecular types. Diagnostic workup remains challenging due to the coexistence of enzymatic and non-enzymatic mechanisms, requiring integrated use of phenotypic antibiotic susceptibility testing (AST), carbapenemase detection assays, molecular diagnostics, and, in selected cases, whole-genome sequencing (WGS). Among treatment, cefiderocol represents the most evidence-supported option for MBL-producing strains. Aztreonam-based combinations offer an alternative treatment option, provided susceptibility is confirmed by synergy testing. Emerging antimicrobials (e.g., taniborbactam-, xeruborbactam-, and zidebactam-containing regimens) and novel strategies such as bacteriophage therapy are regarded as promising alternatives. Evidence for combination therapy remains limited and should be individualized. Conclusions MBL-producing P. aeruginosa requires an integrated, mechanism-based diagnostic and therapeutic strategy incorporating local epidemiology, rapid diagnostics and optimized antimicrobial selection. Ongoing development of novel agents and precision microbiology tools is expected to further refine clinical management.