IDSA 2026 Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections

Overall gram-negative resistance rates have plateaued, but the carbapenemases driving carbapenem resistance have shifted, with NDM expanding alongside KPC and reshaping treatment considerations across the Enterobacterales.

Empiric use of novel agents should follow patient-level risk and unit-level epidemiology, while a shared vocabulary for carbapenem-resistant Enterobacterales and their carbapenemases underpins every subsequent treatment decision.

Rapid molecular testing from positive blood cultures delivers actionable resistance data within hours, and knowing when each result arrives, and which are suppressed, shortens the time to effective therapy.

NDM has diversified and disseminated faster than any prior carbapenemase through mobile genetic elements and distinctive enzyme properties, yet KPC persists, requiring clinicians to account for both in therapeutic planning.

Aztreonam-avibactam pairs a monobactam spared by NDM with an inhibitor of its companion enzymes, offering optimized pharmacodynamics and simpler administration, though NDM-specific clinical data remain limited.

Elevated MICs, NDM-mediated hydrolysis, and a concerning clinical mortality signal have prompted experts to question whether cefiderocol warrants equal standing with aztreonam-avibactam for NDM-producing Enterobacterales.

In critically ill patients receiving continuous renal replacement therapy, aggressive early dosing guided by effluent rate and close pharmacist partnership helps protect drug exposure when MICs already approach the breakpoint.

Penicillin-binding protein 3 alterations in NDM-producing E. coli can compromise both aztreonam-avibactam and cefiderocol simultaneously, while tetracycline derivatives retain a narrow role in carefully selected scenarios.

Cefepime-zidebactam pairs a familiar cephalosporin with a beta-lactam enhancer that targets a second penicillin-binding protein, producing encouraging preclinical activity against carbapenem-resistant organisms ahead of clinical availability.

Ceftazidime-avibactam and meropenem-vaborbactam remain reliable options for KPC producers, ceftazidime-avibactam is favored for OXA-48-like enzymes, and the US withdrawal of imipenem-relebactam narrows the available choices.

Because multiple overlapping mechanisms drive resistance in Pseudomonas aeruginosa, clinicians must test every relevant novel agent, with ceftolozane-tazobactam favored for difficult-to-treat resistant pneumonia.

After distinguishing true infection from colonization, the updated guidance positions sulbactam-durlobactam combined with a carbapenem as the clearly preferred regimen for carbapenem-resistant Acinetobacter baumannii.

Cefiderocol's first-line recommendation for Stenotrophomonas maltophilia rests on compelling preclinical data that historic agents lack, but sparse clinical evidence supports initial combination therapy in critically ill patients.

Securing formulary access to novel gram-negative agents depends on local epidemiology, outcome data, and electronic order safeguards, communicated clearly to committees that often lack infectious diseases expertise.

Early collaboration with microbiology laboratories, reflex testing algorithms, and mechanism-based teaching help ensure that new antimicrobials reach the right patients and that resistance results are interpreted correctly.

Effective stewardship of novel gram-negative agents pairs restriction with deliberate promotion of timely empiric use in high-risk patients, keeping optimized outcomes, rather than limitation, as the central goal.