Therapeutic strategies against biofilm-associated multidrug-resistant Klebsiella pneumoniae and Acinetobacter baumannii in ventilator-associated pneumonia.

Ventilator-associated pneumonia remains one of the most common and severe healthcare associated infections in critically ill patients receiving mechanical ventilation. Among the predominant causative pathogens, multidrug-resistant Klebsiella pneumoniae and Acinetobacter baumannii pose a major clinical challenge due to their extensive antimicrobial resistance, environmental persistence, and ability to form biofilms on endotracheal tubes and other medical devices. Biofilm formation is central to VAP pathogenesis, facilitating bacterial adhesion, immune evasion, reduced antimicrobial penetration, and protective niches that support metabolic dormancy, persister-cell formation, and horizontal gene transfer. These mechanisms promote bacterial survival, recurrent infection, prolonged hospitalization, increased healthcare costs, and mortality. Resistance in K. pneumoniae and A. baumannii is mediated by multiple mechanisms, including β-lactamase production, efflux pump overexpression, reduced outer membrane permeability, target-site modification, and acquisition of mobile resistance determinants. The interaction between AMR and biofilm- associated persistence substantially compromises antimicrobial efficacy, particularly against carbapenem-resistant strains. Although recent advances have expanded treatment options, outcomes remain suboptimal in established biofilm-associated infections. This review examines the epidemiology, clinical burden, resistance mechanisms, biofilm mediated persistence, and host-pathogen interactions underlying MDR K. pneumoniae and A. baumannii associated VAP. Particular emphasis is placed on current therapeutic approaches and emerging anti-biofilm strategies, including antimicrobial-coated devices, nanotechnology-based interventions, matrix-disrupting enzymes, antimicrobial peptides, and anti-virulence approaches targeting quorum sensing and biofilm maturation. Understanding the interplay between AMR, biofilm persistence, and therapeutic failure is critical for developing more effective strategies to prevent and manage MDR-VAP.