By Stan Deresinski, MD, FACP, FIDSA
Synopsis: The activity of newer beta-lactam/beta-lactamase combination antibiotics depends on the specific type of carbapenemase carried by carbapenem-resistant Enterobacterales.
Source: Papp-Wallace KM, Sader HS, Maher JM, et al. Aztreonam-avibactam demonstrates potent activity against carbapenem-resistant Enterobacterales collected from US medical centers over a 6-year period (2017-2022). Open Forum Infect Dis. 2025;12(5):ofaf250.
Papp-Wallace and colleagues examined the in vitro activity of various antibiotics against carbapenem-resistant Enterobacterales (CRE) isolates from 62 U.S. medical centers in 2017-2022. Susceptibility testing was done using the reference (Clinical and Laboratory Standards Institute [CLSI]) broth microdilution method (but with iron-depleted media for cefiderocol testing). European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints were used for interpreting aztreonam-avibactam results since CLSI criteria were not then available, and U.S. Food and Drug Administration (FDA) breakpoints were used for tigecycline for the same reason. CRE accounted for just 511 (0.9%) of the 54,576 isolates, with a carbapenemase detected by whole genome sequencing in 82.6% of the 511. The rank order of activity against CREs was aztreonam-avibactam (98.4% susceptible) > cefiderocol (94.7%) = tigecycline (94.7%) > ceftazidime-avibactam (89.2%) > meropenem-vaborbactam (86.7%) > imipenem-relebactam (81.6%).
The most frequently detected carbapenemase was blaKPC at 68.7%, followed by blaNDM at 8.6% and blaOXA-48-like at 3.1%, followed by small numbers of several others. Seven of the 50 isolates carrying a metallo-beta-lactamase (MBL) also carried a second carbapenemase.
The beta-lactam/beta-lactamase (BL/BLI) combination antibiotics tested (aztreonam-avibactam, ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-relebactam) were active against 92.8% to 99.4% of isolates carrying only class A carbapenemases (largely blaKPC), as were cefiderocol and tigecycline. Among the isolates carrying MBLs, 98.0% were susceptible to aztreonam-avibactam, while for tigecycline and cefiderocol, this proportion was 92.0% and 74.0%, respectively, with the rest being significantly less active.
All 12 isolates carrying only a class D carbapenemase (mostly blaOXA-48-like) were each susceptible to aztreonam-avibactam, ceftazidime-avibactam, and cefiderocol, while 83% were susceptible to tigecycline and 16.7% were susceptible to meropenem-vaborbactam and to imipenem-relebactam.
Testing the 69 CRE that did not carry a carbapenemase found that 88.8% to 96.6% were susceptible to all the BL/BLI combinations and to tigecycline, with ceftazidime-avibactam and aztreonam-avibactam leading the pack at 94.4% and 96.6%, respectively.
Commentary
The results of this study generally are consistent with previous reports and confirm that we now have a number of antibiotics active against CRE, both those carrying a carbapenemase and those lacking such an enzyme. At the same time, there are a number of newer antibiotics waiting in the wings.
This study also confirms that, while other factors such as porin changes, efflux pump alterations, and mutations in penicillin binding proteins also may play roles, the activity of the individual BL/BLI varies depending on the specific type of carbapenemase. For CRE carrying only class A enzymes (think KPC), ≥ 92.8% were susceptible to all the BL/BLIs tested, with 98.9% and 99.4% susceptible to ceftazidime-avibactam and aztreonam-avibactam, respectively. In addition, 96.7% were susceptible to tigecycline. In contrast, only aztreonam-avibactam and tigecycline had high levels of activity against CRE carrying class B carbapenemases (MBLs) — 90% and 92%, respectively, while 74% were susceptible to cefiderocol.
Aztreonam-avibactam was approved by the FDA in February 2025 for the treatment of complicated intraabdominal infection in combination with metronidazole in adults. For treatment of infections due to CRE carrying MBLs, a current often-used approach has been to use the three-drug combination of ceftazidime-avibactam and aztreonam, which presumably has the same level of activity against these organisms.
Finally, the lack of susceptibility of CRE carrying class D carbapenemases (mostly OXA-48-like) to carbapenem BL/BLIs while simultaneously being 100% susceptible to aztreonam-avibactam, ceftazidime-avibactam, and cefiderocol is, to some extent, consistent with the limited hydrolytic activity of the enzyme against advanced generation cephalosporins.
Stan Deresinski, MD, FACP, FIDSA, is Clinical Professor of Medicine, Stanford University.
The activity of newer beta-lactam/beta-lactamase combination antibiotics depends on the specific type of carbapenemase carried by carbapenem-resistant Enterobacterales.
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