Editorial: Advances in combating antimicrobial resistance: focus on diagnosis, therapy, and prevention

(https://www.frontiersin.org/research-topics/70036/advances-in-combatingantimicrobial-resistance-focus-on-diagnosis-therapy-and-prevention)The Escalating Threat of Antimicrobial Resistance: Global and ICU Epidemiology Antimicrobial resistance (AMR) has emerged as one of the most pressing public health threats of the 21 st century. The World Health Organization (WHO) has projected that without effective interventions, AMR could claim 10 million lives annually by 2050, surpassing cancer as a leading cause of death and imposing a cumulative economic burden of $100 trillion globally (1). The clinical landscape of AMR is particularly dire in intensive care units (ICUs), where the convergence of critically ill patients, extensive use of invasive devices, and high selective pressure from broad-spectrum antibiotics creates an ideal environment for the emergence and dissemination of multidrug-resistant organisms (MDROs) and carbapenemresistant organisms (CROs) (2,3).Infections caused by carbapenem-resistant Enterobacteriaceae (CRE), carbapenemresistant Acinetobacter baumannii (CRAB), carbapenem-resistant Pseudomonas aeruginosa (CRPA), and vancomycin-resistant Enterococci (VRE) are associated with devastating clinical outcomes (4,5). A systematic analysis from the GBD 2021 Antimicrobial Resistance Collaborators revealed that bacterial AMR directly caused 1.14 million deaths in 2021 and was associated with 4.71 million deaths globally (1). In ICU settings, patients with CRO infections experience prolonged mechanical ventilation, extended ICU and hospital stay (often exceeding 20-30 days), exorbitant healthcare costs (2-3 times higher than susceptible infections), and mortality rates ranging from 40% to over 60% for CRE and CRAB infections (6)(7)(8).The health economic burden is also staggering. A recent multicenter study across 10 countries estimated that the excess cost per CRO infection ranges from $20,000 to $120,000, driven by the need for combined use of broad-spectrum antibiotics, prolonged use of extracorporeal life support devices, enhanced infection control measures, and prolonged rehabilitation (9). Moreover, the erosion of last-line antibiotics has forced clinicians to rely on older, more toxic agents such as colistin and tigecycline, further compromising patient outcomes. This Research Topic, Advances in Combating Antimicrobial Resistance: Focus on Diagnosis, Therapy, and Prevention, brings together 19 articles from dozens of submissions that address this multifaceted crisis across three interdependent pillars. The contributions herein collectively illuminate a transition from reactive, empiric management to proactive, precisionbased countermeasures.A fundamental obstacle in AMR management has been the reliance on traditional culturebased methods, which require 48-72 hours for pathogen identification and an additional 24-48 hours for antimicrobial susceptibility testing (AST). This delay forces clinicians to initiate empiric broad-spectrum therapy, inadvertently driving further resistance. In response, rapid diagnostic tests (RDTs) have revolutionized the field, enabling same-day pathogen identification and resistance gene detection directly from clinical specimens. Meanwhile, the process of blood culture is constantly being improved to shorten turn around time (TAT) (10,11).Several articles in this Research Topic showcase diagnostic innovations. Yu and colleagues developed a deep learning algorithm based on endoscopic features for rapid Helicobacter pylori infection status assessment, reducing reliance on multiple biopsies and culture confirmation. Beyond molecular panels, metagenomic next-generation sequencing (mNGS) and CRISPR-based assays represent the next frontier. mNGS enables unbiased detection of virtually almost all pathogens in a single test, proving invaluable for culture-negative infections, unexpected or fastidious pathogens, and polymicrobial communities (12,13). CRISPR-based diagnostics offer rapid, low-cost, point-of-care detection with high specificity. The application of these advanced diagnostics is moving us from educated guesswork to precise pathogen identification, forming the bedrock of modern antimicrobial stewardship. After nearly a decade of clinical application, mNGS has demonstrated its advantages over traditional detection methods in the rapid and accurate identification of pathogens. In the future, it will be further localized and efforts will be made to build multi-disciplinary teams (MDT) for the treatment of infections. Together, they will work to accurately interpret relevant reports, contributing to improved patient outcomes.Parallel to rapid phenotypic profiling, understanding the spatial architecture of polymicrobial infections is critical, as standard diagnostic cultures often disrupt complex microbial communities. In this context, ribosomal fluorescence in situ hybridization (FISH) serves as an indispensable tool for the direct, culture-independent visualization of bacterial biofilms within host tissues. As pioneered by Swidsinski and colleagues, the deployment of sequence-specific fluorescent oligonucleotide probes enables the identification of structured, pathogen-specific consortia that otherwise evade conventional mono-infectious diagnostic paradigms (14). By combining strict taxonomic identification with exact morphological localization, FISH-based diagnostic frameworks bypass the limitations of routine microbiology, offering crucial insights into biofilm-mediated resistance and guiding targeted, localized therapeutic interventions.Confronted with pan-resistant bacteria, replenishing the therapeutic pipeline is an urgent clinical necessity. This Research Topic presents real-world evidence on both established and emerging agents, as well as non-antibiotic strategies.β -lactam/ β -lactamase inhibitor (BLBLI) combinations, including ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, imipenem-relebactam and sulbactamdurlobactam. These agents have demonstrated efficacy against CROs (15). However, resistance to even these new agents has already emerged, underscoring the relentless adaptability of microbes (16). Fang and colleagues provide a granular view of in-host co-colonization and bloodstream infection by distinct classical and hypervirulent carbapenem-resistant Klebsiella Pneumoniae (CRKP) clones harboring a homologous blaKPC-2 plasmid, highlighting horizontal resistance transfer and the potential need for combination or sequential therapies.Non-Antibiotic Therapeutic Strategies. Beyond traditional antibiotics, innovative approaches are gaining traction. Kart and colleagues, in their mini-review, explore encapsulated probiotics as antimicrobial agents, detailing delivery mechanisms against MDR pathogens. This approach leverages microbiome modulation to combat infection while preserving beneficial commensals. Bacteriophage therapy, though not featured directly in this collection, represents a longconsidered option for untreatable infections. Phages are viruses that specifically lyse bacteria, offering narrow-spectrum activity that spares the microbiota. Similarly, monoclonal antibodies targeting bacterial toxins or surface antigens and immunomodulatory agents are promising adjunctive strategies that move therapy beyond direct microbicidal action to holistic host support (17). Understanding resistance-virulence co-evolution is critical for therapeutic development. Lin and colleagues, in a comprehensive review, dissect the co-evolution of resistance and virulence in K. pneumoniae liver abscess, focusing on hypervirulent variants and the therapeutic dilemmas posed by concurrent carbapenem resistance and high virulence. These strains, often associated with the rmpA and rmpA2 genes, cause invasive infections in healthy individuals and are increasingly reported worldwide.To outpace the rapid evolution of MDR pathogens, the therapeutic pipeline must expand beyond classical bactericidal or bacteriostatic scaffolds toward targets less prone to conventional resistance mechanisms. Among these alternative strategies, disrupting prokaryotic ion channels represents a highly promising, yet relatively underexplored, paradigm. Bacterial mechanosensitive (MS) channels (such as MscL and MscS) and voltage-gated potassium/calcium transport systems are crucial for maintaining cellular turgor, pH homeostasis, and membrane potential. Pharmacological manipulation of these channels -either via the design of channel blockers that trigger osmotic or metabolic collapse, or through MscL agonists that induce uncontrolled leakage of essential cytoplasmic osmolytes -effectively cripples bacterial viability. Crucially, because these ion systems also regulate the energetic requirements of transmembrane efflux pumps, the application of ion channel blockers has been shown to synergistically reverse drug resistance by preventing the extrusion of co-administered conventional antibiotics and enhancing macrophage-mediated killing of intracellular pathogens (18).Beyond individual cellular homeostasis, targeting ion channel dynamics offers a powerful approach to dismantling complex bacterial biofilm architectures. It has been established that bacteria within biofilms utilize long-range electrical signaling, mediated by coordinated waves of potassium ion efflux, to communicate metabolic stress and synchronize defense behaviors between the interior and periphery of the community. By integrating ion channel modulators into anti-biofilm regimens, this electrochemical communication network can be effectively short-circuited, leaving the biofilm vulnerable to host immune clearance and standard antimicrobials (19). Complementing this biophysical approach, other non-antibiotic strategies featured in this special issue include the deployment of predatory bacteria, such as Bdellovibrio bacteriovorus, which act as "living antibiotics" to physically consume Gram-negative pathogens without triggering receptor-mediated resistance. Additionally, the use of engineered antimicrobial peptides (AMPs) combined with membrane-disrupting agents bypasses traditional metabolic resistance pathways altogether, highlighting a multifaceted future for nontraditional anti-infective discovery (20).Optimizing Existing Agents: PK/PD and TDM. Simply prescribing the right antibiotic is insufficient, achieving adequate exposure at the infection site is paramount. The pathophysiological alterations in sepsis augmented renal clearance (ARC), capillary leak, organ dysfunction, and extracorporeal circuits lead to highly variable antibiotic concentrations (21).Therapeutic drug monitoring (TDM) of antibiotics, particularly for vancomycin and aminoglycosides, has been standard practice. This Research Topic expands this concept to βlactams and other time-dependent antibiotics, demonstrating that a substantial proportion of critically ill patients fail to achieve target pharmacokinetic/pharmacodynamics (PK/PD) indices with standard dosing, and that TDM-guided adjustment improves clinical outcomes. Modelinformed precision dosing (MIPD) using Bayesian algorithms represents the next leap forward, enabling individualized dosing from the outset rather than reactive adjustments.Prevention remains the most sustainable and cost-effective strategy to combat AMR. This Research Topic emphasizes multi-level prevention, from individual prescribers to global policy.AMS programs optimize antibiotic use to maximize clinical benefit while minimizing unintended consequences. Alsalhani and colleagues present a critical integration of One Health perspectives into dental antibiotic stewardship in Saudi Arabia, revealing that inappropriate prescribing in dentistry significantly contributes to community resistance. Their survey of 457 dentists found that 68% prescribed antibiotics for conditions not indicated by guidelines, highlighting an urgent target for stewardship expansion.A systematic review and meta-analysis by Huang et al. on risk factors for CRKP infection synthesizes data from 28 studies (n=12,847 patients).Key modifiable risk factors included prior antibiotic exposure (OR 3.42, 95% CI 2.18-5.36), ICU admission (OR 2.89, 95% CI 1.92-4.35), mechanical ventilation (OR 3.12, 95% CI 2.01-4.84), and central venous catheterization (OR 2.54, 95% CI 1.67-3.86). These findings enable targeted IPC measures, including admission screening for high-risk patients, enhanced environmental disinfection, and contact precautions. Zhao and colleagues highlight a specific high-risk population, demonstrating that multidrug-resistant Clostridioides difficile isolate ST81 is prominent in hematological patients (41.7% of isolates from this population). This finding advocates for routine screening and enhanced barrier precautions in immunocompromised hosts, where standard infection control may be insufficient.