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Antimicrobial-resistant Gram-negative infections
Background
Overview
Definition
Antimicrobial-resistant Gram-negative infections are difficult-to-treat infections caused by Gram-negative bacteria that have developed resistance to multiple antibiotics. Multidrug-resistant isolates are defined as non-susceptible to at least one agent in ≥ 3 relevant antimicrobial categories. Extensively drug-resistant isolates are defined as non-susceptible to at least one agent in all but ≤ 2 relevant antimicrobial categories. Pandrug-resistant isolates are defined as non-susceptible to all relevant agents. Non-susceptibility is determined by vitro antimicrobial susceptibility testing and includes results categorized as resistant, intermediate, or non-susceptible.
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Pathophysiology
Gram-negative bacteria acquire resistance through several mechanisms, including the production of enzymes (such as β-lactamases, AmpC β-lactamases, extended-spectrum β-lactamases, and carbapenemases) degrading antibiotics, efflux pumps expelling antimicrobial agents from bacterial cells and reducing intracellular drug concentrations, mutations in target sites such as DNA gyrase or ribosomal subunits decreasing drug binding and efficacy, and reduced permeability of the outer membrane, often due to porin loss or modification, limiting antibiotic entry. Horizontal gene transfer via plasmids, transposons, or integrons facilitates the dissemination of resistance genes across bacterial populations.
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Epidemiology
The incidence of antimicrobial-resistant infections in the US is estimated at 2.8 million cases annually. An estimated 1.3 million deaths per year worldwide are directly attributable to antimicrobial-resistant pathogens, including over 35,000 deaths in the US. Most common antimicrobial-resistant Gram-negative pathogens are Enterobacterales (extended-spectrum β-lactamase-producing, AmpC β-lactamase-producing, third-generation cephalosporin-resistant, carbapenem-resistant), P. aeruginosa (difficult-to-treat resistance), A. baumannii (carbapenem-resistant), and S. maltophilia.
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Risk factors
Risk factors include recent hospitalizations, particularly in ICUs, antibiotic exposure within the past 3 months, high antibiotic resistance rates in the community or care facility, immunosuppression, and existing comorbidities.
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Disease course
Antimicrobial-resistant Gram-negative bacteria can cause severe, difficult-to-treat infections, including complicated UTIs, severe pneumonia with respiratory failure, intra-abdominal infections, bloodstream infections, and sepsis, resulting in prolonged hospital stay and increased mortality.
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Guidelines
Key sources
The following summarized guidelines for the management of antimicrobial-resistant Gram-negative infections are prepared by our editorial team based on guidelines from the Infectious Diseases Society of America (IDSA 2024), the Surgical Infection Society (SIS 2024), the European Committee on Infection Control (EUCIC/ESCMID 2023,2019), and the European Society for Microbiology and Infectious Diseases (ESCMID 2021).
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Medical management
General principles: as per ESCMID 2021 guidelines, use optimal antibiotic dosing schemes with attention to side effects, especially with the old antibiotics (polymyxins and aminoglycosides).
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Management of Enterobacterales infections (ESBL-producing)
Management of Enterobacterales infections (AmpC beta-lactamase-producing)
Management of Enterobacterales infections (third-generation cephalosporin-resistant)
Management of Enterobacterales infections (carbapenem-resistant)
Management of P. aeruginosa infections (carbapenem-resistant)
Management of P. aeruginosa infections (with difficult-to-treat resistance)
Management of A. baumannii infections (carbapenem-resistant)
Management of S. maltophilia infections
Perioperative care
Perioperative decolonization, colorectal surgery: as per ESCMID/EUCIC 2023 guidelines, consider obtaining rectal screening to identify extended-spectrum cephalosporin-resistant Enterobacterales carriers before colorectal surgery, according to local epidemiology.
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Perioperative decolonization (urologic surgery)
Perioperative decolonization (solid organ transplantation)
Perioperative decolonization (timing and duration)