Victoria Birlutiu, Rares-Mircea Birlutiu
Antimicrobial resistance is now documented in a substantial proportion of laboratory-confirmed bacterial infections worldwide, and although the most extreme extensively drug-resistant (XDR) and pandrug-resistant (PDR) phenotypes are concentrated among Gram-negative bacilli, resistance in Gram-positive cocci continues to rise and remains a major determinant of outcomes in severe infection. This structured comprehensive narrative review, based on a documented search of PubMed/MEDLINE, Scopus and Web of Science to June 2026, is confined to the three Gram-positive cocci of greatest clinical importance-Staphylococcus aureus, Streptococcus pneumoniae and Enterococcus faecium-and summarises current global and European surveillance data for this organisms, describes the principal molecular mechanisms responsible for resistance to β-lactams, glycopeptides, fluoroquinolones, oxazolidinones, lipopeptides, tetracyclines, folate-pathway inhibitors, macrolides-lincosamides-streptogramins and aminoglycosides, and reviews the therapeutic options and investigational agents that may extend the treatment repertoire against multidrug-resistant (MDR) Gram-positive cocci. Surveillance indicators for the three species are compared side by side, and the agents discussed are separated according to whether they are licensed, clinically evaluated but not widely licensed, or still preclinical. Its scope is deliberately narrower than that of pan-bacterial accounts of antimicrobial resistance: it concentrates on the determinants that routine molecular confirmation does not detect, on the divergent pathogen-specific trajectories visible in recent surveillance, and on the distinction between agents supported by randomised evidence and those still at the discovery stage. Our review is structured rather than systematic; the PRISMA 2020 flow diagram is used as a reporting template only, and no claim of PRISMA compliance is made.