A practical guide to treating ESBL-E, AmpC-E, CRE, DTR Pseudomonas aeruginosa, CRAB and Stenotrophomonas maltophilia
Estimated reading time: 6–7 minutes
Primary source: Infectious Diseases Society of America (IDSA), 2026 Guidance on the Treatment of Antimicrobial-Resistant Gram-Negative Infections. The supplied guidance reflects evidence and expert consensus current to 1 March 2026.
Key takeaways
- Treatment should be guided by the organism, resistance mechanism, infection site and antimicrobial susceptibility.
- Newer agents expand options for ESBL-E, CRE and CRAB, including gepotidacin, cefepime–enmetazobactam, aztreonam–avibactam and sulbactam–durlobactam.
- Antimicrobial resistance alone does not require longer treatment; IV-to-oral transition remains appropriate in selected clinically stable patients.
What does the guidance cover?
The IDSA guidance addresses six major antimicrobial-resistant Gram-negative groups:
| Pathogen/resistance phenotype | Abbreviation |
|---|---|
| Extended-spectrum β-lactamase-producing Enterobacterales | ESBL-E |
| AmpC β-lactamase-producing Enterobacterales | AmpC-E |
| Carbapenem-resistant Enterobacterales | CRE |
| P. aeruginosa with difficult-to-treat resistance | DTR P. aeruginosa |
| Carbapenem-resistant Acinetobacter baumannii | CRAB |
| Stenotrophomonas maltophilia | S. maltophilia |
The document covers adults and children, although its dosing table is for adults. It is an evidence-informed guidance document rather than a GRADE-based clinical practice guideline and is primarily written for US practice.
Treatment recommendations generally assume that the causative organism has been identified and susceptibility to the proposed antibiotic demonstrated.
How should ESBL-E infections be treated?
Treatment depends strongly on infection site.
| Clinical setting | Main treatment approach |
|---|---|
| Uncomplicated UTI | Nitrofurantoin, TMP-SMX, gepotidacin, pivmecillinam or sulopenem; single-dose aminoglycoside is another option |
| Complicated UTI | TMP-SMX, ciprofloxacin or levofloxacin when susceptible |
| cUTI when these cannot be used | Cefepime–enmetazobactam or a carbapenem |
| Invasive/non-urinary infection | Carbapenem preferred; cefepime–enmetazobactam is an alternative |
| Critical illness or hypoalbuminaemia | Meropenem or imipenem preferred over ertapenem |
Carbapenems therefore remain central to invasive ESBL-E infection. In critically ill or hypoalbuminaemic patients, meropenem or imipenem is preferred over ertapenem.
Piperacillin–tazobactam is not preferred for invasive ESBL-E infection, while cefepime is generally not suggested for ESBL-E complicated UTI or invasive disease.
What is the approach to AmpC-E?
For organisms at moderate risk of clinically significant inducible AmpC production — including Enterobacter cloacae complex, Klebsiella aerogenes, Citrobacter freundii and Hafnia alvei — antibiotic stability against AmpC is important.
| Clinical situation | Approach |
|---|---|
| Cefepime MIC ≤8 µg/mL | Cefepime preferred if an ESBL gene has not been identified |
| Invasive infection | Ceftriaxone, cefotaxime and ceftazidime generally avoided for moderate-risk organisms |
| Uncomplicated UTI | Nitrofurantoin or TMP-SMX preferred |
| Carbapenem-resistant AmpC-E | Consider newer β-lactams according to susceptibility |
Cefepime has low AmpC induction potential and relative stability against AmpC hydrolysis.
Broader agents such as ceftazidime–avibactam, aztreonam–avibactam, meropenem–vaborbactam, imipenem–relebactam and cefiderocol should generally be preserved for organisms requiring their broader resistance coverage.
For CRE, why does the carbapenemase matter?
CRE should not be treated as a single resistance phenotype. Identifying the underlying carbapenemase can directly influence antibiotic selection.
| CRE mechanism | Important treatment options |
|---|---|
| KPC-producing CRE | Meropenem–vaborbactam, ceftazidime–avibactam or imipenem–relebactam |
| MBL-producing CRE | Aztreonam–avibactam |
| Non-carbapenemase CRE with retained carbapenem susceptibility | Active extended-infusion carbapenem may be appropriate |
| No active conventional carbapenem | Newer agent selected according to resistance mechanism and AST |
For KPC-producing CRE, the newer β-lactam/β-lactamase inhibitor combinations have become important treatment options.
For metallo-β-lactamase-producing organisms, aztreonam–avibactam provides a targeted approach because aztreonam is stable to MBL hydrolysis while avibactam protects it from accompanying serine β-lactamases.
How is DTR Pseudomonas aeruginosa treated?
Several newer β-lactams retain activity against selected DTR P. aeruginosa isolates.
| Antibiotic | Role |
|---|---|
| Ceftolozane–tazobactam | Important antipseudomonal option |
| Ceftazidime–avibactam | Active against selected resistant isolates |
| Imipenem–relebactam | Option when susceptible |
| Cefiderocol | Alternative with broad resistant Gram-negative activity |
Treatment should be guided by AST and infection site.
Treatment-emergent resistance can occur with newer β-lactams, making repeat susceptibility testing important when P. aeruginosa is recovered again during or after treatment.
What is preferred for CRAB?
CRAB remains particularly difficult to treat because multiple resistance mechanisms frequently coexist.
For invasive CRAB, the guidance favours sulbactam–durlobactam combined with imipenem or meropenem.
| Strategy | Role |
|---|---|
| Sulbactam–durlobactam + imipenem/meropenem | Preferred approach |
| High-dose ampicillin–sulbactam | Alternative sulbactam-based strategy when sulbactam–durlobactam is unavailable |
| Cefiderocol | Alternative in selected circumstances |
Sulbactam has intrinsic activity against A. baumannii. Durlobactam protects sulbactam from clinically relevant β-lactamases, allowing that activity to be retained.
The suggested adult sulbactam–durlobactam dose in patients with normal renal and hepatic function is 2 g IV every six hours infused over three hours, with renal-function-based adjustment.
What about Stenotrophomonas maltophilia?
An important first step is determining whether an isolate represents infection or colonisation.
Potential treatment options include cefiderocol, minocycline, TMP-SMX, levofloxacin and aztreonam–avibactam, depending on susceptibility and clinical context.
The evidence base is less robust than for several other resistant Gram-negative infections, so microbiological results must be interpreted alongside the clinical syndrome.
Which newer antibiotics are particularly important?
Several newer or recently available therapies expand treatment options for resistant Gram-negative infections.
| Antibiotic | Class/type | Important role |
|---|---|---|
| Gepotidacin | Oral triazaacenaphthylene | Selected uncomplicated ESBL-E UTI |
| Pivmecillinam | Oral penicillin; prodrug of mecillinam | Selected uncomplicated ESBL-E UTI |
| Sulopenem | Oral penem | Selected uncomplicated ESBL-E UTI |
| Cefepime–enmetazobactam | Cephalosporin + β-lactamase inhibitor | ESBL-E cUTI; alternative for invasive ESBL-E |
| Aztreonam–avibactam | Monobactam + β-lactamase inhibitor | Particularly relevant to MBL-producing CRE |
| Sulbactam–durlobactam | Sulbactam + β-lactamase inhibitor | Preferred sulbactam-based strategy for invasive CRAB |
New oral options
Gepotidacin, pivmecillinam and sulopenem expand oral choices for selected uncomplicated ESBL-E urinary infections.
Pivmecillinam has been used internationally for decades and received US approval in April 2024. The guidance reports activity against >90% of ESBL-E isolates.
Sulopenem received US approval in October 2024, with the guidance reporting activity against >95% of ESBL-E isolates.
These indications should not be automatically extrapolated to bacteraemia or other invasive infections.
Newer targeted β-lactam combinations
Cefepime–enmetazobactam provides another option against ESBL-producing Enterobacterales and can be used as an alternative to carbapenems in selected invasive ESBL-E infections.
Aztreonam–avibactam is particularly important for MBL-producing Gram-negative organisms, where its complementary mechanism can overcome otherwise difficult β-lactam resistance.
For CRAB, sulbactam–durlobactam provides a more targeted sulbactam-based approach and is used with imipenem or meropenem for invasive infection.
When can patients switch from IV to oral therapy?
Antimicrobial resistance does not automatically require prolonged intravenous treatment.
Oral transition can be considered when:
| Requirement | Practical consideration |
|---|---|
| Susceptibility | An active oral antibiotic is available |
| Clinical stability | Patient is haemodynamically stable |
| Drug exposure | Adequate concentrations are expected at the infection site |
| Absorption | Gastrointestinal absorption is reliable |
For invasive ESBL-E infections, oral ciprofloxacin, levofloxacin or TMP-SMX may be considered after an appropriate clinical response when susceptibility is demonstrated.
Does resistance require longer treatment?
Not necessarily.
The guidance states that treatment durations for AMR infections generally do not need to differ from those used for infections caused by susceptible organisms.
Duration should instead reflect the infection, clinical response, immune status and source control.
When inactive empirical therapy has been given for infections other than an improving uncomplicated bladder UTI, treatment should generally be changed to an active agent and duration counted from the start of active therapy.
Clinical takeaway
The 2026 IDSA guidance reinforces a mechanism- and site-directed approach to antimicrobial-resistant Gram-negative infections.
Carbapenems remain central to invasive ESBL-E disease; cefepime has an important role in appropriate AmpC-E infections; CRE treatment increasingly depends on identifying the resistance mechanism; and newer agents provide additional options for DTR P. aeruginosa, MBL-producing CRE and CRAB.
New oral therapies also broaden options for selected ESBL-E urinary infections. However, newer antibiotics should be used within the infection sites and patient populations supported by the evidence rather than extrapolated broadly.
Full reference
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. Infectious Diseases Society of America. 2026. The supplied guidance states that its evidence and expert consensus are current to 1 March 2026.