Treatment Strategies for Drug-Resistant Gram-Negative Infections: Updates from the 2026 IDSA Guidance

Against the backdrop of antimicrobial resistance (AMR) emerging as a global health crisis, with projections suggesting that it could cause up to 10 million deaths annually by 2050, updating evidence-based treatment regimens has become a critical task for healthcare professionals. In response to this need, the Infectious Diseases Society of America (IDSA) has published the 2026 update to its Guidance on the Treatment of Antimicrobial-Resistant Gram-Negative Infections, replacing previous versions.

This article provides an in-depth review of antibiotic selection recommendations for six key groups of drug-resistant Gram-negative bacteria, emphasizing the need to individualize treatment based on bacterial identification and the specific underlying resistance mechanism.

1. Extended-Spectrum β-Lactamase-Producing Enterobacterales (ESBL-E)

ESBL-E are bacteria that inactivate most penicillins, cephalosporins, and aztreonam.

• Urinary tract infections (UTIs): For uncomplicated urinary tract infections (uUTIs), preferred options include nitrofurantoin and TMP-SMX. Single-dose aminoglycosides (amikacin, gentamicin, tobramycin, or plazomicin) are also recommended because of the extremely high concentrations these agents achieve in the urine.
• Invasive infections: Carbapenems (meropenem, imipenem, or ertapenem) remain the first-line treatment for infections outside the urinary tract. However, in critically ill patients or those with hypoalbuminemia (<2.5 g/dL), meropenem or imipenem is preferred over ertapenem because of concerns regarding altered pharmacokinetics of highly protein-bound drugs.
• Important note on piperacillin-tazobactam: The 2026 IDSA Guidance recommends avoiding this agent for invasive ESBL-E infections even when antimicrobial susceptibility testing (AST) indicates susceptibility. This recommendation is based on clinical trial data showing higher mortality compared with carbapenems.

2. AmpC β-Lactamase-Producing Enterobacterales (AmpC-E)

The recommendations focus on species at moderate risk of inducible AmpC production, including E. cloacae, K. aerogenes, and C. freundii.

• Preferred strategy: Cefepime is the preferred antibiotic when the MIC is ≤8 µg/mL because of its stability against AmpC-mediated hydrolysis.
• Avoid ceftriaxone: Ceftriaxone (as well as cefotaxime and ceftazidime) should be avoided for invasive infections caused by these species because of the risk of resistance emerging during therapy (approximately 20%).

3. Carbapenem-Resistant Enterobacterales (CRE)

Treatment of CRE depends largely on the specific carbapenemase mechanism involved:

• KPC-producing CRE: Newer agents such as ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-relebactam are preferred options. Among these, meropenem-vaborbactam is slightly favored because available data indicate a lower rate of emergence of resistance during treatment (<3%) compared with ceftazidime-avibactam (approximately 10%).
• MBL-producing CRE (e.g., NDM): Aztreonam-avibactam and cefiderocol are the two preferred first-line options. If aztreonam-avibactam is unavailable, ceftazidime-avibactam plus aztreonam may be used in combination.
• OXA-48-like-producing CRE: Ceftazidime-avibactam is preferred because avibactam has potent inhibitory activity against OXA-48, whereas vaborbactam and relebactam do not.

4. Difficult-to-Treat Resistant Pseudomonas aeruginosa (DTR P. aeruginosa)

This group includes strains that are nonsusceptible to traditional antibiotics, including carbapenems and piperacillin-tazobactam.

• First-line options: Ceftolozane-tazobactam, ceftazidime-avibactam, and imipenem-relebactam are preferred options for infections outside the urinary tract.
• Preferred option for pneumonia: Ceftolozane-tazobactam is favored by IDSA experts for the treatment of pneumonia caused by DTR P. aeruginosa because of its favorable penetration into the epithelial lining fluid of the lungs (50% compared with 30% for the other agents).
• MBL mechanism: For MBL-producing strains (VIM, IMP, or NDM), cefiderocol is the only preferred antibiotic with demonstrated efficacy.

5. Carbapenem-Resistant Acinetobacter baumannii (CRAB)

CRAB is one of the most challenging pathogens to treat because of its diverse resistance mechanisms.

• Preferred regimen: A combination of sulbactam-durlobactam and a carbapenem (imipenem or meropenem). Durlobactam protects sulbactam from hydrolysis, allowing sulbactam to target PBP1 and PBP3, while the carbapenem provides additional activity through binding to PBP2.
• Alternative options: If sulbactam-durlobactam is unavailable, combination therapy with agents such as cefiderocol, minocycline, or polymyxin B may be considered.

6. Stenotrophomonas maltophilia

• Preferred option: Cefiderocol monotherapy is the preferred option based on animal-model data demonstrating superior bactericidal activity and nearly 100% in vitro susceptibility.
• Alternative options: Combination antibiotic therapy (such as aztreonam-avibactam, levofloxacin, minocycline, or TMP-SMX) is recommended until the patient’s clinical condition stabilizes.

Appropriate Use of Antibiotics

Summary Table of Preferred Antibiotic Options for Invasive Infections

The following table summarizes common drug-resistant pathogens and the antibiotics recommended by the 2026 IDSA Guidance (applicable to patients with normal renal and hepatic function).

Pathogen	Preferred Antibiotics	Alternative Antibiotics
ESBL-E (Invasive)	Carbapenems (meropenem, imipenem, ertapenem)	Cefepime-enmetazobactam
AmpC-E (Invasive)	Cefepime (if MIC ≤8 µg/mL)	Carbapenems
CRE (KPC)	Ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam	Aztreonam-avibactam, cefiderocol
CRE (NDM/MBL)	Aztreonam-avibactam, cefiderocol	Ceftazidime-avibactam + aztreonam
DTR P. aeruginosa	Ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-relebactam	Cefiderocol
CRAB (Invasive)	Sulbactam-durlobactam + carbapenem	Cefiderocol, minocycline, polymyxin B (in combination)
S. maltophilia	Cefiderocol	Aztreonam-avibactam, levofloxacin, minocycline, TMP-SMX (in combination)

Conclusion

The 2026 IDSA Guidance emphasizes that antimicrobial resistance is a rapidly evolving field. Antibiotic selection should be based not only on pathogen identification but also on drug penetration at the site of infection and the patient’s safety profile.

Note: This guidance reflects the available evidence and expert consensus as of March 1, 2026. Clinicians should consult specific dosing recommendations and contraindications based on each patient’s individual clinical condition.

As a leading pharmaceutical supply partner, we are proud to provide products containing active ingredients included among the antibiotics recommended by IDSA, such as aminoglycosides (amikacin, tobramycin, and netilmicin) and levofloxacin, supporting healthcare professionals in the global fight against multidrug-resistant pathogens.

References

Tamma PD, Bonomo RA, Heil EL, Justo JA, Satlin MJ, Mathers AJ. Infectious Diseases Society of America 2026 Guidance on the Treatment of Antimicrobial-Resistant Gram-Negative Infections. Clinical Infectious Diseases. Published online August 8, 2026. doi:10.1093/cid/ciag481.