INTRODUCTION Hospital-acquired infections, also known as nosocomial infections, are a major threat to patient safety worldwide.1 Among the causative agents, ESKAPE pathogens–Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species – are particularly concerning due to their ability to resist multiple antibiotics, leading to increased morbidity, mortality, and healthcare costs. Classical mechanisms of resistance are well established; however, recent studies reveal emerging resistance trends, including plasmid-mediated colistin resistance, evolving carbapenemase variants, and hetero-resistance phenotypes, which further complicate management.2 Concurrently, diagnostic gaps, especially in resource-limited settings, hinder timely and effective intervention. This article focuses on recently identified resistance mechanisms in ESKAPE pathogens, highlights diagnostic advancements, and reviews emerging therapeutic strategies, providing a concise overview for clinicians and researchers to address this pressing challenge. MECHANISM OF ANTIMICROBIAL RESISTANCE Antimicrobial resistance (AMR) in ESKAPE pathogens arises through multiple well-established mechanisms, including β-lactamase production, efflux pump overexpression, target modification, and biofilm formation. While these classical pathways underpin resistance to commonly used antibiotics, recent research has identified emerging mechanisms that are rapidly exacerbating the clinical burden. Plasmid-mediated colistin resistance (mcr genes) has spread across Enterobacterales, compromising last-resort therapy.3 Evolving carbapenemase variants (e.g. NDM, OXA, KPC subtypes) exhibit enhanced enzymatic activity and broadened substrate specificity, rendering many β-lactams ineffective. Heteroresistance, where subpopulations exhibit transient resistance, complicates susceptibility testing and treatment decisions. In addition, accelerated horizontal gene transfer, including mobile genetic elements, enables rapid dissemination of resistance determinants among hospital strains.4 Biofilm persistence further protects pathogens from antimicrobial exposure and host defenses, contributing to chronic infections. These emerging mechanisms collectively challenge conventional therapeutic strategies. Highlighting the urgent need for rapid detection, surveillance, and innovative treatment approaches.3-9 CLINICAL IMPACT AND GLOBAL BURDEN The clinical burden of ESKAPE pathogens is substantial, particularly in intensive care and immunocompromised populations. Multidrug-resistant (MDR) complicates therapy, leading to prolonged hospital stays, increased healthcare costs, and elevated mortality rates; the instance, carbapenem-resistant Enterobacterales and Acinetobacter infections are associated with mortality rates exceeding 30% in high-risk cohorts.6 In resource-limited settings such as India, the absence of widespread point-of-care diagnosis delays pathogen identification and susceptibility testing, resulting in inappropriate empirical therapy and further amplification of resistance. By contrast, facilities with rapid molecular assays, syndromic panels, or whole-genome sequencing report faster initiation of targeted therapy and improved clinical outcomes.7 Current diagnostic tools include disk diffusion and broth microdilution, but their turnaround time is often insufficient for timely clinical decision-making. Emerging rapid molecular approaches, including multiple polymerase chain reaction and genomic surveillance, provide actionable data within hours, enabling early detection of resistance determinants such as mcr genes or carbapenemases.8 Incorporating these technologies into clinical practice is essential for guiding therapy, preventing outbreaks, and reducing morbidity and mortality. Addressing diagnostic gaps alongside stewardship interventions is therefore critical to mitigating the global threat posed by ESKAPE pathogens. EMERGING THERAPEUTIC STRATEGIES The rise of MDR ESKAPE pathogens has necessitated novel therapeutic strategies beyond conventional antibiotics. New β-lactam/β-lactamase inhibitor combinations, such as ceftazidime-avibactam and meropenem-vaborbactam, have demonstrated efficacy against resistant strains and are already approved in clinical practice, making them the most immediately implementable option.9,10 Bacteriophage therapy offers pathogen-specific killing and biofilm disruption, but its clinical application remains limited by regulatory hurdles, production scalability, and the need for individualized phage selection. Antimicrobial photodynamic therapy (aPDT) provides localized eradication of planktonic and biofilm bacteria without promoting resistance; however, its use is largely restricted to topical or surface infections. CRISPR-Cas-based strategies represent a promising experimental approach for targeted bacterial genome editing, though they are currently confined to preclinical models. Comparative analysis suggests that while new β-lactam combinations are ready for immediate deployment, phage therapy and aPDT may serve as adjunctive or niche interventions, and CRISPR-based tools hold future potential pending further research. Integrating these therapies with rapid diagnostics and antimicrobial stewardship is essential to optimize outcomes, limit the spread of resistance, and guide precision treatment in both resource-rich and resource-limited settings. CONCLUSION AMR among ESKAPE pathogens continues to challenge contemporary healthcare systems worldwide. Emerging resistance mechanisms, including plasmid-mediated colistin resistance, evolving carbapenemases, and hetero-resistance, exacerbate treatment difficulties. Couples with diagnostic gaps in resource-limited settings, these pathogens contribute to increased morbidity and mortality. Integration of rapid molecular diagnostics, targeted novel therapies, and stringent antimicrobial stewardship is essential to mitigate this threat. Focused research on scalable interventions, combined with timely clinical implementation, offers a pathway to curb the spread of resistance and improve patient outcomes in both high and low-resource healthcare environments. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
Patil et al. (Wed,) studied this question.