The global rise of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Gram-negative bacteria has emerged as a critical public health concern, particularly in the management of complex infections, such as osteomyelitis, healthcare-associated ventriculitis, device-associated infections, and implant-associated infections. These hard-to-treat infections frequently occur in vulnerable patient populations, including those with diabetes, immune compromise, trauma, or surgical implants. The therapeutic arsenal against these infections is rapidly diminishing due to evolving resistance mechanisms, which not only hampers clinical outcomes but also increases healthcare costs and patient morbidity. As a result, there is an urgent need for concerted research efforts to understand, diagnose, and manage these infections effectively.

This article collection seeks to comprehensively address the multifaceted challenges posed by MDR and XDR Gram-negative pathogens—including Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella spp.—in the context of difficult to treat infections. We invite manuscripts that delve into the molecular mechanisms of resistance, improvements in diagnostic modalities, evaluation of novel and existing therapeutic options, identification of prognostic factors influencing patient outcomes, and application of preventive practices. By focusing on both cutting-edge research and clinical studies, this collection aims to enhance the evidence base for managing these infections, ultimately guiding improved patient care and informing future antimicrobial stewardship strategies.

To gather further insights into Gram-negative bacterial infections, we encourage articles addressing, but not limited to, the following themes:

• Reviews on the epidemiology and management of difficult-to-treat MDR/XDR Gram-negative infections
• Original research exploring molecular mechanisms of drug resistance in E. coli, Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella spp.
• Studies evaluating diagnostic tools and biomarkers for identifying resistant pathogens in bone infections, device-associated infections, and implant-associated infections
• Studies assessing the efficacy of novel or combination antibiotic therapies in difficult-to-treat infections by MDR/XDR Gram-negative bacteria, such as bone infections, healthcare-associated ventriculitis, and implant-associated infections
• Meta-analyses of treatment and/or outcomes MDR/XDR Gram-negative bacterial infections
• Reports on the impact of antimicrobial stewardship interventions in orthopedic settings, neurosurgery settings, and patients with devices and implants
• Articles focused on infection prevention practices and strategies in the above settings and infections

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Unraveling Resistance: Challenges in Treating MDR and XDR Gram-Negative Infections