The Infectious Diseases Society of America has updated its guidance on treating antimicrobial-resistant gram-negative infections, incorporating newer therapies and evolving evidence across six major pathogen groups.
Published in Clinical Infectious Diseases, the 2026 guidance addresses six groups of resistant gram-negative pathogens: extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-E); AmpC beta-lactamase-producing Enterobacterales (AmpC-E); carbapenem-resistant Enterobacterales (CRE); Pseudomonas aeruginosa with difficult-to-treat resistance (DTR P. aeruginosa); carbapenem-resistant Acinetobacter baumannii (CRAB); and Stenotrophomonas maltophilia. It replaces earlier versions of IDSA’s antimicrobial resistance treatment guidance.
Pranita D. Tamma, MD, MHS, of the University of Pennsylvania Perelman School of Medicine in Philadelphia, and five other infectious diseases specialists developed the guidance for U.S. clinical practice. It applies to adults and children, although specific dosing guidance is provided only for adults, and reflects evidence and expert consensus through March 1, 2026. The panel based its guidance on a literature review, clinical expertise and expert consensus; it did not use GRADE methodology.
Susceptibility testing remains central
The recommendations assume that the organism causing the infection has been identified and shown to be susceptible to the antibiotic being considered. When several antibiotics are expected to work equally well, clinicians should also weigh safety, tolerability, cost, ease of administration and formulary availability.
Empiric treatment should take into account the severity and source of infection, prior culture and susceptibility results, recent antibiotic use and local resistance patterns. Treatment should then be reassessed once the organism and its susceptibility profile are known. The guidance also emphasizes distinguishing true infection from colonization to avoid unnecessary antibiotic use.
Treatment does not generally need to be longer simply because the infection is caused by a resistant organism. When appropriate, patients may transition from intravenous to oral therapy if an effective oral antibiotic is available, the patient is hemodynamically stable and the drug is expected to be adequately absorbed and reach the infection site.
Preferred therapies depend on resistance mechanism
For invasive ESBL-E infections outside the urinary tract, carbapenems remain preferred. Meropenem or imipenem are favored over ertapenem in critically ill patients or those with hypoalbuminemia. Oral ciprofloxacin, levofloxacin or trimethoprim-sulfamethoxazole may be used as step-down therapy once susceptibility is confirmed and the patient is clinically stable.
For AmpC-E infections, cefepime is preferred when the organism is susceptible. This includes infections caused by Enterobacter cloacae complex, Klebsiella aerogenes, Citrobacter freundii and Hafnia alvei, which are considered at moderate risk of clinically significant AmpC production. Ceftriaxone is generally avoided for invasive infections caused by these organisms because resistance can emerge during treatment.
Treatment of CRE infections depends on the specific resistance mechanism. For KPC-producing infections, preferred options include ceftazidime-avibactam, imipenem-relebactam and meropenem-vaborbactam. Aztreonam-avibactam and cefiderocol are preferred for infections caused by New Delhi metallo-beta-lactamase-producing organisms, while ceftazidime-avibactam is preferred for OXA-48-like-producing isolates.
Newer agents expand options for difficult-to-treat infections
Four newer beta-lactam agents may retain activity against DTR P. aeruginosa: cefiderocol, ceftazidime-avibactam, ceftolozane-tazobactam and imipenem-relebactam. The guidance suggests susceptibility testing for all four when DTR P. aeruginosa is identified. For infections outside the urinary tract, ceftazidime-avibactam, ceftolozane-tazobactam and imipenem-relebactam are preferred, with ceftolozane-tazobactam favored for pneumonia.
For invasive CRAB infections, sulbactam-durlobactam combined with imipenem or meropenem is the preferred treatment. In a randomized trial cited in the guidance, 28-day survival was 81% with sulbactam-durlobactam plus imipenem compared with 68% with colistin plus imipenem; clinical cure rates were 62% and 40%, respectively. If sulbactam-durlobactam is not immediately available, high-dose ampicillin-sulbactam combined with at least one additional active agent may be used as temporary bridging therapy until sulbactam-durlobactam plus a carbapenem can be initiated.
Cefiderocol monotherapy is preferred for invasive S. maltophilia infections, although the recommendation is based largely on animal-model rather than clinical outcomes data. Aztreonam-avibactam, preferably combined with a second active agent, is an alternative.
Amy J. Mathers, MD, a guidance coauthor and professor of medicine in the Division of Infectious Diseases and International Health at the University of Virginia School of Medicine, said the guidance is intended to help clinicians make treatment decisions in a rapidly changing field.
“Antimicrobial resistance is a moving target. As we assess newer therapies, often with limited or imperfect data, determining how best to place and use these agents requires weighing multiple factors and is a constantly evolving science,” said Dr. Mathers in an interview with this news organization. “Our goal with this guidance is to put the clinician faced with treating a serious infection caused by a drug-resistant pathogen at the center of that difficult decision and provide practical, evidence-informed suggestions to help navigate it.”
Dr. Tamma reported no disclosures. Dr. Mathers reported no current industry relationships; she receives research funding from the National Institute of Allergy and Infectious Diseases, the Centers for Disease Control and Prevention, and the Food and Drug Administration, and serves as a volunteer for the Clinical and Laboratory Standards Institute. Other panel members reported research funding, consulting or advisory roles, editorial activities, honoraria, stock ownership, data and safety monitoring board service, or other relationships with government, nonprofit and industry organizations.
