BACKGROUND
Carbapenem-resistant Enterobacterales (CRE) represent heterogeneous resistance mechanisms with distinct clinical and public health implications (1, 2). Among these mechanisms, carbapenemases drive the spread of CRE. The type of carbapenemase affects treatment options, as fewer agents are active against CRE with NDM and other metallo-β-lactamases compared to KPC, the historically predominant carbapenemase in U.S. CRE (3).
OBJECTIVE
We describe trends in carbapenemase-producing CRE (CP-CRE) clinical isolates reported to CDC’s Antimicrobial Resistance Laboratory Network (4) from January 2019 through December 2023.
METHODS & FINDINGS
We developed an open cohort of U.S. states that mandated submission of all carbapenem-resistant Klebsiella spp., Escherichia coli, and Enterobacter spp. isolates before July 1, 2020, and contributed a minimum of 36 consecutive months of data for this analysis (Table S1). CP-CRE had ≥1 carbapenemase (KPC, NDM, VIM, IMP, and OXA-48-like) detected or demonstrated carbapenemase production but did not have a carbapenemase identified (File S1).
Statistical methods are detailed in File S2. Annual aggregate and state-specific incidence rates were estimated for CP-CRE overall and by carbapenemase using isolate counts as the numerator and U.S. Census population as the denominator. Age-adjusted incidence rates were standardized to the 2010 U.S. population. Temporal trends were assessed with indicator variables for year using a Poisson generalized linear model with robust sandwich estimators and log-link, adjusting for age group (0-18/19-64/65-79/≥80 years). We conducted multiple sensitivity analyses, including comparing our open cohort to incidence rates in all U.S. states. Analyses were performed in R, version 4.4.0. This activity was reviewed by CDC, deemed not research, and was conducted consistent with applicable federal law and CDC (45 C.F.R. part 46.102(l)(2), 21 C.F.R. part 56; 42 U.S.C. §241(d); 5 U.S.C. §552a; 44 U.S.C. §3501 et seq).
The open cohort increased from 24 states in 2019 to 29 states during 2021-2023, representing 35% of the U.S. population (Table S2). The annual unadjusted CRE incidence was 18% higher in 2023 vs. 2019 (IRR:1.18 [95% CI: 1.14, 1.22]).
Between 2019 and 2023, the age-adjusted incidence of CP-CRE increased 69% (IRR:1.69 (95% CI:1.61, 1.78) [Table 1, Table S3]), and the age-adjusted incidence of NDM-CRE increased 461% (IRR:5.61 [95% CI:4.96, 6.36], Figure 1A, Table S3–S5), with increases of NDM-CRE observed across 48% of states within our cohort (Table S6). The incidence of OXA-48-like-CRE also increased (IRR:1.50 [95% CI:1.17, 1.94]). In contrast, KPC-CRE incidence decreased from 2019 to 2020 and then rose; rates in 2023 were similar to 2019. National trends for unadjusted aggregate incidence rates were consistent with our cohort; removing outlier states from the open cohort showed similar trajectories, but the magnitude of change was smaller (Table S7, Fig. S1).
Table 1.
Unadjusted and Age-Adjusted CP-CRE Incidence Rates per 100,000 Persons Across Open Cohort of U.S. States with Required CRE Isolate Submission, 2019-2023
| Year | No. of States Included | Unadjusted Population | No. of CP-CRE* Cases | Unadjusted† Incidence/100,000 Persons (95% CI) | Age-Adjusted ‡ Incidence/100,000 Persons (95% CI) |
|---|---|---|---|---|---|
| 2019 | 24 | 102,253,036 | 2,267 | 2.22 (2.13, 2.31) | 1.98 (1.90, 2.07) |
| 2020 | 28 | 115,487,153 | 1,903 | 1.65 (1.58, 1.72) | 1.48 (1.41, 1.54) |
| 2021 | 29 | 117,033,977 | 2,534 | 2.17 (2.08, 2.25) | 1.91 (1.84, 1.99) |
| 2022 | 29 | 117,566,458 | 3,137 | 2.67 (2.58, 2.76) | 2.35 (2.27, 2.44) |
| 2023 | 29 | 118,211,191 | 4,341 | 3.67 (3.56, 3.78) | 3.16 (3.07, 3.26) |
Footnote: Delta method was used to calculate confidence intervals for incidence rates
CP-CRE, includes Klebsiella spp., Enterobacter spp., and Escherichia coli with the presence of mCIM+/PCR−, blaKPC, blaNDM, blaVIM, blaIMP, and blaOXA-48-like carbapenemase gene.
U.S. 2019-2023 Census Population Estimates (U.S. Census Bureau Population Division. Vintage 2019-2023 Special Tabulation)
Age-adjusted rates were standardized to the U.S. 2010 Census Population Estimates (U.S. Census Bureau Population Division. Vintage 2010 Special Tabulation)
Abbreviations: CP-CRE, carbapenemase-producing carbapenem-resistant Enterobacterales
Figure 1.
Unadjusted CP-CRE Incidence Rates per 100,000 Persons Across an Open Cohort of U.S. States with Required CRE Isolate Submission, by A) Carbapenemase Gene and B) by Organism Grouping and Carbapenemase Gene, 2019-2023
From 2019 to 2023, the unadjusted incidence for CP-CRE and NDM-CRE increased across all genera and among OXA-48-like-Klebsiella spp. (Figure 1B, Table S8). In contrast, KPC-Klebsiella spp. incidence decreased (IRR:0.91 [95% CI:0.85, 0.98]). By 2023, NDM was identified in 27% of carbapenem-resistant E. coli, 24% of carbapenem-resistant Klebsiella spp., and 6% of carbapenem-resistant Enterobacter spp. (Fig. S2).
DISCUSSION
In a cohort of 29 states with mandated CRE isolate submission, the incidence of CP-CRE clinical cultures surged between 2019 and 2023, primarily due to NDM and, to a lesser extent, OXA-48. By 2023, NDM-CRE incidence was comparable to KPC-CRE, and NDM had become the most common carbapenemase in E. coli. The rise of NDM and OXA-48, historically less common in the U.S., added to the existing burden of KPC-CRE. The increasing diversity of carbapenemases among CRE complicates treatment, as most new FDA-approved antimicrobial agents active against CRE target specific carbapenemase classes. Consequently, treatment should be tailored to the carbapenemase type, but carbapenemase testing is limited in clinical laboratories, and public health laboratory results may not be timely for clinical decisions (3, 5). Additionally, susceptibility testing for aztreonam-avibactam and cefiderocol, the only β-lactam-based agents active against NDM, is not widely available.
Our analysis has limitations. The most populous states, including California, Florida, New York, and Texas, were excluded; however, in a sensitivity analysis, findings from our cohort aligned with national trends. While patients may have contributed multiple isolates, this is unlikely to impact relative changes in incidence among different mechanisms. Passive isolate submission may have resulted in some isolates not being submitted for testing.
The changing epidemiology of CP-CRE poses significant challenges for managing CRE infections. Understanding local CRE epidemiology and integrating mechanism testing into laboratory workflows may help ensure patients receive timely, appropriate therapy.
Supplementary Material
Acknowledgements.
We thank public health laboratories in the CDC AR Laboratory Network for testing CRE isolates and providing the data used in this analysis. We greatly appreciate the Healthcare-Associated Infections/Antimicrobial Resistance programs at the Connecticut Department of Public Health, Georgia Department of Public Health, Massachusetts Department of Public Health, Maryland Department of Health, Nebraska Department of Health and Human Services, North Carolina Department of Health and Human Services, South Carolina Department of Public Health, Tennessee Department of Health, Virginia Department of Health, and Washington State Department of Health, for evaluating the percent of isolates tested from out-of-state residents to inform limitations of our approach.
Financial Support.
No funding external to the Centers for Disease Control and Prevention was provided for this study.
Footnotes
Disclaimer. The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Use of trade names is for identification only and does not imply endorsement by the Public Health Service or by the U.S. Department of Health and Human Services.
Conflict of interest. All authors report no conflicts of interest relevant to this article.
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