Treatment of Antimicrobial Resistant Gram-Negative Infections

Introduction

• Updated projections describing the burden of morbidity and mortality attributable to antimicrobial resistance (AMR).
• Harmonized definitions of uncomplicated and complicated urinary tract infections with the 2025 IDSA Guidelines on the Management and Treatment of Complicated Urinary Tract Infections.
• Added a reference outlining dosing recommendations for newer β-lactam agents based on a consensus statement from United States pediatric infectious diseases pharmacists to provide suggested dosing of antibiotics for AMR infections in children.
• Added clarifying language indicating that preferred and alternative antibiotic options are presented in alphabetical order within the “Suggested Approach” sections; additional nuance regarding prioritization among agents is provided in the corresponding “Rationale” sections.
• Updated Table 1 (antibiotic dosing suggestions) to reflect the most current available evidence.
• Updated Table 2 with 2026 CLSI antibiotic susceptibility breakpoint data.
• Updated the Supplemental Material to align with the updated Table 1.

Extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E)

• Revised the criteria for presumed ESBL production in E. coli, K. pneumoniae, and K. oxytoca to ceftriaxone MIC ≥4 µg/mL, reflecting updated evidence.
• Updated estimates of the prevalence of ESBL production among E. coli isolates in the United States.
• Added references describing the molecular epidemiology and species-specific prevalence of non-CTX-M ESBL enzymes.
• Added information regarding the FDA-approved agent gepotidacin for the treatment of ESBL-E infections.
• Added information regarding the FDA-approved agent pivmecillinam for the treatment of ESBL-E infections.
• Added information regarding the FDA-approved agent oral sulopenem for the treatment of ESBL-E infections.
• Added information on the suggested role of cefepime-enmetazobactam for the treatment of ESBL-E infections.
• Added information regarding the FDA-approved agent intravenous fosfomycin for the treatment of ESBL-E infections.
• Expanded discussion of the approximate susceptibility percentages of ESBL-E isolates to non-β-lactam agents used empirically for uncomplicated UTIs.
• Revised suggestions to include piperacillin-tazobactam as an alternative treatment option for complicated UTIs.
• Added references to ongoing clinical trials evaluating piperacillin-tazobactam and cefmetazole (a cephamycin) for the treatment of ESBL-E bloodstream infections.
• Added additional references describing recent comparative effectiveness studies for the treatment of ESBL-E infections.

AmpC-producing Enterobacterales (AmpC-E)

• Updated information regarding the molecular epidemiology of ampC genes in Enterobacterales in the United States.
• Added Hafnia alvei as an organism associated with a moderate risk of clinically significant AmpC production.
• Added language indicating that, in cases of non-severe infection in which ceftriaxone was initiated empirically and the patient demonstrates clinical improvement with adequate source control, continuation of ceftriaxone for completion of therapy may be reasonable.
• Added additional references describing recent comparative effectiveness studies for the treatment of AmpC-E infections.
• Added additional data supporting the suggestion that piperacillin-tazobactam may be suboptimal for invasive infections caused by Enterobacterales at moderate risk for clinically significant inducible AmpC production.
• Added information regarding the FDA-approved agent gepotidacin for the treatment of AmpC-E infections.
• Added information regarding the FDA-approved agent pivmecillinam for the treatment of AmpC-E infections.
• Added information regarding the FDA-approved agent oral sulopenem for the treatment of AmpC-E infections.
• Added information on the suggested role of cefepime-enmetazobactam for the treatment of AmpC-E infections.

Carbapenem-Resistant Enterobacterales (CRE)

• Updated discussion of the evolving molecular epidemiology of CRE in the United States.
• Added information regarding the FDA-approved agent gepotidacin for the treatment of CRE infections.
• Added information regarding the FDA-approved agent pivmecillinam for the treatment of CRE infections.
• Added information regarding the FDA-approved agent intravenous fosfomycin for the treatment of CRE infections.
• Added information describing susceptibility rates of CRE isolates to non-β-lactam antibiotics that may retain activity against CRE infections.
• Added preclinical and clinical data comparing ceftazidime-avibactam and meropenem-vaborbactam for infections caused by KPC-producing Enterobacterales.
• Added information regarding the FDA-approved agent aztreonam-avibactam for the treatment of NDM-producing infections.
• Added a brief discussion of aztreonam-avibactam and ceftazidime-avibactam plus aztreonam for NDM-producing Enterobacterales, noting either is reasonable for the treatment of NDM-producing Enterobacterales infections, with a slight preference for aztreonam-avibactam.
• Added preclinical and clinical data comparing aztreonam-avibactam and cefiderocol for infections caused by NDM-producing Enterobacterales.
• Updated discussion of known mechanisms of resistance to newer β-lactam agents among CRE isolates.

Pseudomonas aeruginosa with difficult-to-treat resistance (DTR P. aeruginosa)

• Added references describing recent comparative effectiveness studies evaluating ceftazidime-avibactam versus ceftolozane-tazobactam, including data supporting preference for ceftolozane-tazobactam in DTR P. aeruginosa pneumonia.
• Added discussion noting that imipenem-cilastatin-relebactam appears to have a similarly high risk of resistance emergence during therapy as ceftazidime-avibactam and ceftolozane-tazobactam.
• Added data from a clinical trial comparing cefiderocol versus alternative therapy for DTR P. aeruginosa bloodstream infections (i.e., “the Game Changer Trial”).
• Removed the question addressing treatment of uncomplicated UTI caused by DTR P. aeruginosa and added a statement on the suggested approach for this rare scenario at the end of the response to the question regarding treatment of complicated UTI.
• Added a question addressing how identification of carbapenemases in P. aeruginosa should influence treatment selection.
• Updated data describing the emergence of resistance to anti-pseudomonal agents.
• Updated discussion regarding the role of nebulized antibiotics; while still not routinely preferred, the suggestion against their use was moderated in light of some data suggesting improved clinical cure with their use.

Carbapenem-resistant Acinetobacter baumannii (CRAB) infections

• Added the term “invasive infections” throughout the CRAB section to clarify that suggestions apply to infection rather than colonization.
• Expanded introductory discussion of resistance mechanisms commonly identified in CRAB isolates.
• Removed questions addressing the general treatment approach for CRAB infections and the role of combination therapy.
• Added information regarding the suggested treatment approach for NDM-producing CRAB infections.
• Added language indicating that the priority for invasive CRAB infections is the administration of sulbactam-durlobactam (in combination with a carbapenem) and alternative options should only be administered as bridge therapy until sulbactam-durlobactam is available.
• Added language that if resistance to sulbactam-durlobactam is exhibited, approaches include the use of two non-sulbactam agents or the addition of sulbactam-durlobactam to cefiderocol.
• Added data from a clinical trial comparing cefiderocol versus alternative therapy for CRAB bloodstream infections (i.e., “the Game Changer Trial”).
• Updated data from observational studies evaluating cefiderocol for invasive CRAB infections.
• Removed questions addressing the role of extended-infusion meropenem or imipenem-cilastatin for CRAB infections.
• Removed questions addressing the role of rifamycins for invasive CRAB infections.
• Updated discussion regarding the role of nebulized antibiotics; while still not routinely preferred, the suggestion against their use was moderated in light of some data suggesting improved clinical cure with their use.

Stenotrophomonas maltophilia Infections

• Removed the question addressing the general treatment approach for infections caused by S. maltophilia.
• Added the term “invasive infections” throughout the section to clarify that suggestions apply to infection rather than colonization.
• Designated cefiderocol monotherapy as the preferred treatment for invasive S. maltophilia infections, with the acknowledgement that this is based on susceptibility data and neutropenic animal studies with very little supportive clinical data.
• Updated data from neutropenic animal studies evaluating the role of cefiderocol in S. maltophilia infections.
• Changed treatment suggestion to aztreonam-avibactam, preferably in combination with a second agent, is an alternative treatment option for invasive S. maltophilia infections.
• Added data from a clinical trial comparing cefiderocol versus alternative therapy for S. maltophilia bloodstream infections (i.e., “the Game Changer Trial”).