Nowadays, antimicrobial resistance (AMR) is a growing global health threat, with carbapenem-resistant Enterobacteriaceae (CRE) posing particular concern due to limited treatment options. In fact, CRE have been classified as a critical priority by the World Health Organization (WHO). Carbapenem resistance results from complex mechanisms, often combining the production of hydrolytic enzymes such as β-lactamases with reduced membrane permeability and efflux system induction. The Ambler classification is an effective tool for differentiating the characteristics of serine-β-lactamases (SβLs) and metallo-β-lactamases (MβLs), including ESβLs (different from carbapenemases), KPC, NDM, VIM, IMP, AmpC (different from carbapenemases), and OXA-48. Recently approved inhibitor drugs, such as diazabicyclooctanones and boronic acid derivatives, only partially address this problem, not least because of their ineffectiveness against MβLs. However, compared with taniborbactam, xeruborbactam is the first bicyclic boronate in clinical development with a pan-β-lactamase inhibition spectrum, including the IMP subfamily. Recent studies explore strategies such as chemical optimization of β-lactamase inhibitor scaffolds, novel β-lactam/β-lactamase inhibitor combinations, and siderophore–antibiotic conjugates to enhance bacterial uptake. A deeper understanding of the mechanistic properties of the active sites enables rational drug design principles to be established for inhibitors targeting both SβLs and MβLs. This review aims to provide a comprehensive overview of current therapeutic strategies and future perspectives for the development of carbapenemase inhibitor drug candidates.

Antimicrobial resistance (AMR) has made multidrug-resistant organisms (MDROs), particularly ESKAPE-E pathogens (including Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp, and Escherichia coli), a major threat to modern medicine. Although novel antibiotics, antimicrobial stewardship, and infection prevention remain essential, such interventions are unlikely to offset projected AMR trends on their own. Vaccines can help to mitigate AMR by preventing infections and reducing antibiotic exposure. WHO estimates that vaccines targeting 23 pathogens (excluding Neisseria gonorrhoea) could reduce global antibiotic need by 22%, equivalent to 2·5 billion defined daily doses annually. In the mRNA era, modular vaccine platforms enable rapid design of protein antigens and multivalent constructs, with emerging preclinical proof of concept against selected bacterial pathogens. In this Personal View, we argue that mRNA vaccines should be considered enabling platforms for selected protein-based MDRO targets rather than universal solutions for antibacterial vaccine development. We propose a microbiome-informed framework that distinguishes systemic protection from mucosal decolonisation and aligns antigen selection, delivery route, and trial endpoints with colonisation dynamics, microbiome resilience, and AMR reduction goals.

Antimicrobial consumption surveillance is central to strategies addressing antimicrobial resistance (AMR), yet indicators for benchmarking national performance remain debated. Defined daily doses (DDDs), while useful for trend monitoring, inadequately reflect prescribing quality when used as comparative metrics. Using European surveillance data (2019-2024), we show that applying the WHO AWaRe classification substantially reshapes country rankings, aligning more closely with resistance epidemiology and AMR-attributable mortality. Countries with high Access-group proportions, rather than low total volumes, achieve superior stewardship outcomes. Volume-based DDD metrics may paradoxically penalise appropriate high-dose short-course or early-switch strategies, as exemplified in the UK and Japan. AWaRe should therefore be interpreted as a governance tool, not a punitive performance score, and applied alongside resistance, case mix, and outcomes data. Integrating risk-stratified, outcome-informed indicators can guide health policy, support harmonised stewardship across the EU, and better translate surveillance into actionable strategies for reducing antimicrobial resistance.