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NDM and OXA 48 like Enterobacterales
The Rise of NDM and OXA-48–Like Enterobacterales in the United States

Released: March 02, 2026

Ryan K. Shields
Ryan K. Shields, PharmD, MS
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Key Takeaways
  • Among CRE isolates, a gradual shift is occurring from dominance of KPC enzymes to NDM and OXA-48, which are resistant to many antibiotic regimens that work against KPC-producing isolates.
  • Identifying the specific mechanism(s) of CRE resistance using diagnostic and resistance testing is crucial to optimizing therapy.

The Changing Face of Carbapenem-Resistant Enterobacterales in the United States
For many years in the US, we could reasonably assume that when a carbapenemase-producing Enterobacterales appeared in microbiology reports, it was likely due to the Klebsiella pneumoniae carbapenemase (KPC) enzyme. This assumption guided empiric therapy, diagnostic interpretation, infection-control practices, and even antibiotic discovery efforts. But that era is quietly ending, and in many regions of the US, it is over entirely.

Increasingly, carbapenem-resistant Enterobacterales (CRE) isolates in US healthcare settings are being driven by metallo-β-lactamases such as New Delhi metallo-β-lactamase (NDM) and, less commonly, OXA-48–like β-lactamases. A surveillance study across 74 US medical centers found that in the 2 years from 2019 to 2021, the frequency of KPC dropped from 73.8% to 57.1%, whereas NDM and OXA-48 rose from 3.8% to 20.4% and 1.3% to 8.2%, respectively.

Major regional shifts have also been reported. In New York City, NDM has surpassed KPC as the most commonly identified carbapenemase. Data from the CDC corroborated this shift, identifying a 461% increase in the age-adjusted NDM rate from 2019 to 2023.

The changing epidemiology has been subtle enough that many healthcare professionals have not yet adjusted their empiric treatment of CRE infections or their mindset around non-KPC β-lactamases. From a clinical standpoint, recognizing the shift from KPC to NDM and OXA-48–like enzymes in CRE is incredibly important to ensure effective treatment. Although bacteria with KPC enzymes generally respond to newer β-lactam/β-lactamase inhibitor combination regimens like ceftazidime/avibactam, meropenem/vaborbactam, and imipenem/relebactam, bacteria with NDM enzymes are not inhibited by any of these newer antibiotic combinations. This underscores the importance of resistance testing to identify the mechanisms of resistance to allow for optimal treatment selection.

Therapeutic Implications of Rising NDM and OXA-48 Rates
From a treatment standpoint, an increased diversity of carbapenemases forces us to think more mechanistically. For NDM-producing CRE, aztreonam-based combination regimens with a β-lactamase inhibitor are effective for isolates that coproduce other β-lactamases. For OXA-48–like producing CRE, cephalosporin-based combination therapies like ceftazidime/avibactam should be prioritized over carbapenem-based combination therapies like meropenem/vaborbactam or imipenem/relebactam. Cefiderocol is an alternative option for CRE that generally retains activity against KPC, NDM, and OXA-48–like enzymes.

As the NDM and OXA-48–like enzymes become more common, the importance of diagnostic stewardship grows. Accurate identification of the underlying cause of carbapenem resistance is the most direct way to ensure the initiation of active therapy and avoid the use of potentially ineffective treatment. Moreover, NDM and OXA-48–like enzymes are highly transmissible within healthcare settings because they reside on mobile genetic elements (ie, transposons on plasmids). Practically speaking, the early identification of NDM and OXA-48–like enzymes is not only essential for treatment, but also for targeted surveillance and to implement infection control practices to limit further spread.

Thus, understanding the molecular mechanisms of resistance is no longer an academic exercise reserved for microbiologists and bacterial resistance enthusiasts. It is foundational knowledge that healthcare professionals must possess to select appropriate treatment for CRE infections.

Looking Ahead
The encouraging news is that therapeutic innovation is responding to the increase in NDM and OXA-48–like enzymes. Newer agents like aztreonam/avibactam and cefiderocol are already available, and several novel agents are progressing through preclinical development. The challenge will be to use these antibiotics judiciously so that their activity is preserved.

Your Thoughts
What testing are you using to determine the mechanisms of resistance and select treatment for CRE? Leave a comment to join the discussion!

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