January 12, 2026
5 min read
It’s Friday afternoon when the question comes in:
“What antibiotic should I use to treat this patient’s Klebsiella pneumoniae? It’s resistant to carbapenems, and there’s a comment from microbiology that says ‘carbapenemase production detected.’ Oh, and it looks like it’s resistant to ceftazidime-avibactam, too.”
Carbapenem resistance can be mediated by carbapenemases, which include both serine beta-lactamases (eg, Klebsiella pneumoniae carbapenemase [KPC] and oxacillinase-48 [OXA-48]) and metallo-beta-lactamases (MBL; eg, New Delhi metallo-beta-lactamase [NDM]). Infections due to carbapenem-resistant Enterobacterales (CRE) are increasing worldwide and are considered an urgent health threat by the CDC. Fortunately, in the last decade, the number of effective antimicrobial options for treating CRE has expanded significantly, but to answer the question above, clinicians must understand the relationship between these various newer agents and the carbapenemases encountered in practice.
The anti-CRE drug renaissance began in 2015 with the approval of ceftazidime-avibactam, which paired an existing beta-lactam with a novel beta-lactamase inhibitor (BLI). Following the same formula, meropenem-vaborbactam and imipenem-cilastatin-relebactam reached the market in 2017 and 2019, respectively. All of these novel BLIs improved beta-lactam activity against KPC-producing bacteria, but none were effective against MBLs. That changed in 2019 with the approval of cefiderocol.
A novel siderophore cephalosporin, cefiderocol uses the iron transport pathway to overcome resistance, and was the first available beta-lactam with activity against MBL-producing pathogens. In 2025, aztreonam-avibactam became the second beta-lactam-based product on the market with MBL activity. Aztreonam is not hydrolyzed by MBLs, and the addition of avibactam shields aztreonam from any serine beta-lactamases that may also be present, broadening the spectrum of the combination to include CRE. With this new approval and new trial data for cefiderocol potentially changing the CRE treatment game, a review of the playing field is warranted.
A game-changer?
Cefiderocol has demonstrated safety and efficacy in both complicated UTIs and nosocomial pneumonia. Unfortunately, despite its potent activity against CRE, including MBL producers, cefiderocol stumbled a bit as a CRE therapy in the CREDIBLE-CR trial. In this phase 3 study comparing cefiderocol with best available therapy for treatment of serious infections due to carbapenem-resistant gram-negative organisms, there were numerically more deaths in the cefiderocol arm at end of study (34% vs. 18%), though imbalances between study groups preclude drawing firm conclusions.
In light of these data, the recently published GAME-CHANGER trial sought to clarify cefiderocol’s role in treating gram-negative bloodstream infections (BSI), including those due to CRE. In this phase 3 clinical trial, 504 adult patients with BSI due to gram-negative pathogens were randomized to cefiderocol (n = 250) or standard of care (SOC, primarily carbapenem or piperacillin-tazobactam; n = 254). In the overall cohort, cefiderocol was non-inferior to SOC for the primary outcome of 14-day mortality (8% cefiderocol vs. 7% SOC), but in the subset of patients with CRE infections, cefiderocol was numerically worse (9/64 [15%] vs. 6/63 [10%]). Similar mortality findings were seen in those with infections specifically due to MBL-producing pathogens (5/16 [31%] cefiderocol vs. 0/11 [0%] SOC).
Overall, the results of GAME-CHANGER confirm that cefiderocol is broadly effective for serious gram-negative infections, including BSIs. But for CRE infections, these results mean there is still plenty of game left to be played before the final whistle.
REVISITing an old drug
The approval of aztreonam-avibactam was based in part on the results of the phase 3 REVISIT trial. In this trial, 422 adult patients with complicated intra-abdominal infection (cIAI), hospital-acquired pneumonia, or ventilator-associated pneumonia were randomized to receive aztreonam-avibactam (with metronidazole for cIAI, n = 282) or meropenem (with or without colistin, n = 140).
Clinical cure at test of cure was achieved in 68.4% of patients in the aztreonam-avibactam arm and 65.7% in the meropenem arm. Mortality at 28 days was also similar between groups (4.3% aztreonam-avibactam vs. 7.1% meropenem). These findings were also reflected in the small subset of patients with confirmed CRE infections (clinical cure 4/13 [30.8%] aztreonam-avibactam vs. 2/6 [33.3%] meropenem). Interestingly, this study was not designed with a formal non-inferiority or superiority hypothesis to test, so all results were descriptive in nature.
Approximately half the CRE isolates in REVISIT were MBL producers; 28-day mortality rates were 14.3% (1/7) for aztreonam-avibactam and 0% (0/3) for meropenem in this subgroup.
Given the potential niche against MBL-producing organisms, the phase 3 ASSEMBLE trial aimed to evaluate the clinical efficacy of aztreonam-avibactam compared with the best available therapy for infections due to confirmed MBL-producing pathogens. Unfortunately, this trial only enrolled 15 patients (12 aztreonam-avibactam, three best available therapy). Clinical cure (41.7% vs. 0%) and 28-day mortality (8.3% vs. 33.3%) both numerically favored aztreonam-avibactam.
The low enrollment in ASSEMBLE and low cure rates among CRE in both trials highlight the challenges of studying and treating infections caused by CRE. Further, the small number of confirmed infections due to CRE limit the ability to draw firm conclusions about aztreonam-avibactam’s utility for these infections. Nevertheless, despite these limitations and the lack of formal statistical hypothesis testing in REVISIT, the results of these trials suggest aztreonam-avibactam is a viable option for managing infections due to CRE.
Nuanced decisions and unusual variants
Although both of these agents may have a role in the treatment of CRE infections, especially those due to MBL-producing bacteria, neither is a panacea for all resistant gram-negative infections. Compared with trial results for cefiderocol, aztreonam-avibactam appears to perform slightly better against MBL-producers and CRE infections in general. However, there are far fewer patients with CRE infections in the aztreonam-avibactam trials, and without head-to-head data, it is not clear that one agent is better than the other. Site of infection, potential copathogens, allergies, and other patient-specific factors can all influence a final treatment decision.
Additionally, the specific mechanism of carbapenem resistance needs to be considered. In the opening case, the isolate was resistant to ceftazidime-avibactam, which could indicate MBL production. However, carbapenemase mutations, such as the D179Y substitution seen in KPCs, can also lead to ceftazidime-avibactam resistance. These KPC variants demonstrate increased affinity for ceftazidime and decreased avibactam binding. Growing data suggest cross-resistance to cefiderocol occurs with these mutations, and aztreonam-avibactam may be affected as well. Consequently, these isolates are likely better treated with an alternative agent, such as meropenem-vaborbactam. Phenotypically, both KPC variants and MBLs can appear resistant to ceftazidime-avibactam, highlighting the need for genotypic testing for resistance mechanisms and phenotypic antimicrobial susceptibility testing to ensure that the most effective treatment is chosen.
In summary, the therapeutic armamentarium for managing gram-negative infections continues to expand, and new data highlight some potential options for some of the most resistant pathogens encountered in practice, including MBL-producing CRE. Increasing specificity of these agents for specific resistance mechanisms, combined with ever-present evolutionary pressure from antibiotic use, necessitates that clinicians keep abreast of current data to ensure optimal therapy is chosen in each case.
For more information:
Gregory B. Tallman, PharmD, MS, BCPS, BCIDP, is a clinical pharmacy specialist in infectious diseases and program director of the PGY2 infectious diseases pharmacy residency at Providence St. Joseph Health. He can be reached at gregory.tallman@providence.org.
Sources/Disclosures
Source:
Expert Submission
References:
- Bassetti M, et al. Lancet Infect Dis. 2020;doi:10.1016/S1473-3099(20)30796-9.
- Bianco G, et al. Eur J Clin Microbiol Infect Dis. 2021;doi:10.1007/s10096-021-04341-z.
- Boattini M, et al. Eur J Clin Microbiol Infect Dis. 2024;doi:10.1007/s10096-024-04958-w.
- Carmeli Y, et al. Lancet Infect Dis. 2024;doi:10.1016/S1473-3099(24)00499-7.
- CDC. Antimicrobial Resistance Threats in the United States, 2021-2022. https://www.cdc.gov/antimicrobial-resistance/data-research/threats/update-2022.html. Published July 2024. Accessed Dec. 16, 2025.
- Daikos GL, et al. JAC Antimicrob Resist. 2025;doi:10.1093/jacamr/dlaf131.
- Hobson CA, et al. Clin Microbiol Infect. 2021;doi:10.1016/j.cmi.2021.04.016.
- Paterson DL, et al. Lancet Infect Dis. 2025;doi:10.1016/S1473-3099(25)00469-4.
- Portsmouth S, et al. Lancet Infect Dis. 2018;doi:10.1016/S1473-3099(18)30554-1.
- Tamma PD, et al. Clin Infect Dis. 2024;doi:10.1093/cid/ciae403.
- Winkler ML, et al. J Antimicrob Chemother. 2015;doi:10.1093/jac/dkv094.
- Wise MG, et al. J Glob Antimicrob Resist. 2024;doi:10.1016/j.jgar.2024.03.020.
- Wunderink RG, et al. Lancet Infect Dis. 2020;doi:10.1016/S1473-3099(20)30731-3.
Disclosures:
Tallman reports no relevant financial disclosures.
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