Clinical Infectious Diseases (CID)Infectious Diseases Society of America 2026 Guidance on the Treatment of Antimicrobial-Resistant Gram-Negative Infections

✅ Guideline Update

The 2026 guidance addresses ESBL-producing and AmpC-producing Enterobacterales, carbapenem-resistant Enterobacterales (CRE), difficult-to-treat resistant Pseudomonas aeruginosa, carbapenem-resistant Acinetobacter baumannii (CRAB), and Stenotrophomonas maltophilia. Treatment selection depends on infection site, susceptibility, resistance mechanism, and patient factors. Published August 8, 2026, the document reflects evidence and consensus through March 1, 2026. It applies to US adult and pediatric practice, but provides dosing only for adults. Its literature review is not necessarily systematic, and formal recommendation-strength and evidence-certainty ratings are absent.

Clinical Considerations

• ESBL infections: Gepotidacin, pivmecillinam, and sulopenem join established preferred options for uncomplicated UTI. Cefepime–enmetazobactam is preferred for complicated UTI when TMP-SMX or fluoroquinolones cannot be used, but remains an alternative outside the urinary tract. Carbapenems remain preferred for invasive ESBL infections; piperacillin–tazobactam is an alternative only for selected noncritically ill, nonbacteremic complicated UTI.
• AmpC infections: Cefepime is preferred for moderate-risk species when MICs are ≤8 µg/mL and an ESBL or its gene has not been identified. Hafnia alvei enters this risk category based primarily on in vitro evidence. Ceftriaxone is generally avoided for invasive disease, with limited continuation exceptions for improving, nonsevere infections with source control.
• CRE treatment is mechanism-specific: KPC producers have three preferred β-lactam combinations, with a slight panel preference for meropenem–vaborbactam. Aztreonam–avibactam or cefiderocol are preferred for NDM producers; ceftazidime–avibactam is preferred for OXA-48-like producers. These choices are not interchangeable across carbapenemase families.
• Difficult-to-treat resistant P. aeruginosa: Ceftolozane–tazobactam is preferred for pneumonia among the preferred newer β-lactams, informed by observational and pharmacologic evidence. Cefiderocol is preferred for metallo-β-lactamase producers. Routine combination therapy is not suggested once an active β-lactam is confirmed; recurrent isolates warrant repeat susceptibility testing.
• Invasive CRAB: Sulbactam–durlobactam plus imipenem or meropenem is preferred. High-dose ampicillin–sulbactam plus another agent is positioned as temporary bridging therapy when access is delayed, not an equivalent ongoing alternative. Other combinations are reserved principally for resistance or interim access needs.
• Invasive S. maltophilia: Cefiderocol monotherapy is preferred, largely on animal-model evidence rather than demonstrated clinical superiority. Aztreonam–avibactam, levofloxacin, minocycline, and TMP-SMX are alternatives generally initiated within combination regimens; supporting clinical data remain limited and inconsistent.

Practice Applications

• Integrate susceptibility results, carbapenemase identification, infection site, and source control into stewardship review; distinguish colonization from infection before targeted treatment.
• Review dosing, loading doses, prolonged infusions, and augmented renal clearance. The adult dosing table assumes normal renal and hepatic function; some regimens differ from approved labeling.
• Evaluate oral transition only when susceptibility, hemodynamic stability, infection-site exposure, and absorption support it. Resistance alone does not justify longer treatment.
• Monitor agent-specific risks, including aminoglycoside or polymyxin nephrotoxicity, IV fosfomycin sodium burden, probenecid interactions, and TMP-SMX renal, hematologic, and electrolyte effects.
• Avoid applying one combination-therapy rule across pathogens: active β-lactam monotherapy generally suffices for CRE and resistant P. aeruginosa, unlike preferred CRAB treatment.