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Observational Study
. 2025 Jul 11;231(6):1489-1501.
doi: 10.1093/infdis/jiae616.

Molecular Epidemiology and Clinical Characterization of Carbapenemase-Producing Enterobacter Species From an International Cohort

Jianping Jiang  1 , Lauren Komarow  2 , Carol Hill  3 , Angelique E Boutzoukas  3 , Blake Hanson  4 , Cesar A Arias  5   6 , Robert A Bonomo  7 , Scott Evans  2 , Yohei Doi  8   9 , Michael J Satlin  10 , Gregory Weston  11 , Eric Cober  12 , Sandra Liliana Valderrama-Beltran  13 , Soraya Salcedo Mendoza  14   15 , Zhengyin Liu  16 , Bettina C Fries  17 , Paul Ananth Tambyah  18 , Henry F Chambers  19 , Vance G Fowler Jr  3 , David van Duin  20 , Barry N Kreiswirth  1 , Liang Chen  1
Affiliations
Observational Study

Molecular Epidemiology and Clinical Characterization of Carbapenemase-Producing Enterobacter Species From an International Cohort

Jianping Jiang et al. J Infect Dis. .

Abstract

Background: Despite the global public health threat posed by carbapenem-resistant Enterobacter spp, clinical and molecular epidemiological studies on international isolates remain scarce. Historically, the taxonomy of Enterobacter has been challenging, limiting our understanding of the clinical characteristics and outcomes of carbapenemase-producing Enterobacter spp infections.

Methods: Hospitalized patients enrolled in the CRACKLE-2 study (ClinicalTrials.gov, NCT03646227) from 2016 to 2018 with cultures positive for carbapenemase-producing Enterobacter spp were included. Clinical and microbiologic data were collected from health records. Whole genome sequencing was performed, and the population structures of selected predominant clones were analyzed.

Results: We enrolled 136 hospitalized patients with carbapenemase-producing Enterobacter spp from 30 hospitals in 7 countries. Among the 136 isolates, 11 Enterobacter spp were identified, with most isolates belonging to E xiangfangensis (n = 81 [60%]) and E hoffmannii (n = 17 [13%]) and carrying blaKPC (n = 106 [78%]) and blaNDM (n = 12 [9%]). Clinical characteristics and outcomes were similar among patients with E xiangfangensis, E hoffmannii, or the other Enterobacter spp. Thirty-day mortality was 20%, and older age at enrollment (adjusted odds ratio, 1.42 [95% confidence interval, 1.08-1.87]) was associated with increased mortality. Sequence type (ST) 171 E xiangfangensis, ST78 E hoffmannii, and ST93 E xiangfangensis were the predominant clones, and the acquisition of fluoroquinolone resistance-associated mutations and carbapenemase-encoding plasmids contributed to their formation and global dissemination.

Conclusions: Our findings demonstrate that E xiangfangensis and E hoffmannii are common species among international carbapenemase-producing Enterobacter spp, potentially linked to the clonal spread of a few predominant clones that have acquired fluoroquinolone resistance and carbapenemase-encoding plasmids.

Keywords: E hoffmannii; E xiangfangensis; carbapenem-resistant Enterobacter spp; clinical characterization; molecular epidemiology.

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Conflict of interest statement

Potential conflicts of interest. All authors report funding support from the ARLG of the NIH and NIAID (grant number UM1AI104681) during the conduct of this study. J. J., L. K., C. H., B. N. K., G. W., E. C., S. L. V.-B., S. S. M., Z. L., and L. C. report an ARLG grant paid to their institution. In addition, and outside of the submitted work, the following authors declare the following: A. E. B. reports NIH grants and contracts paid to her institution, research support from the Thrasher Research Foundation, and support from the Biogen foundation. B. H. reports an NIH/NIAID grant K01AI148593-01 paid to his institution. C. A. A. reports grants and contracts from NIH/NIAID, paid to his institution (1 P01 AI152999, R01 AI148342, R01 AI134637, T32 AI141349, K24 AI121296, U19 AI144297, R01 AI150685, R21 AI151536); payments to him for UpToDate royalties; reimbursement of meeting attendance and speaking from the Infectious Diseases Society of America (IDSA), American Society for Microbiology, Society of Hospital Epidemiology of America, European Society for Clinical Microbiology and Infectious Diseases, Mérieux Foundation, Sociedad Argentina de Infectologia, Sociedad Chilena de Infectologia, Sociedad Colombiana de Infectologia, Panamerican Society for Infectious Diseases, and Brazilian Society for Infectious Diseases; reviewer participation as part of the NIH grant review study sections; travel expenses from the IDSA Board of Directors, and for Editor in Chief for Antimicrobial Agents and Chemotherapy; unpaid participation includes World Health Organization Antibacterial Pipeline Advisory Group and participation on the IDSA Board of Directors. R. A. B. reports grants and contracts, paid to his institution, by VenatoRx, Wockhardt, and Merck; payments made to him by Pfizer to moderate meeting sessions; a provisional patent with Case Western Reserve University on the development of boronic acid transition state inhibitors for β-lactamases; and membership on a data and safety monitoring board (DSMB) as a logistics associate for the Division of Microbiology and Infectious Diseases Clinical Research Operations and Management Support, Safety Oversight Committee Support, and Technical Resources International, Inc. S. E. reports grants from the NIAID, NIH, CDC, and De Gruyter (Editor in Chief for Statistical Communications in Infectious Diseases); royalties from Taylor & Francis; consulting fees from Genentech, AstraZeneca, Takeda, Microbiotix, Johnson & Johnson, Endologix, ChemoCentryx, Becton Dickinson, Atricure, Roviant, Neovasc, Nobel Pharma, Horizon, International Drug Development Institute, and SVB Leerink; payments from Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION); meeting support from the US Food and Drug Administration, the Deming Conference on Applied Statistics, the Clinical Trial Transformation Initiative, the Council for International Organizations of Medical Sciences, the International Chinese Statistical Association Applied Statistics Symposium, and the Antimicrobial Resistance and Stewardship Conference; and board member participation for the NIH, the Breast International Group, the University of Pennsylvania, Washington University, Duke University, Roche, Pfizer, Takeda, Akouos, Apellis, Teva, Vir, DayOneBio, Alexion, Tracon, Rakuten, AbbVie, GSK, Eli Lilly, Nuvelution, Clover, FHI Clinical, Lung Biotech, SAB Biopharm, Advantagene, Candel, and Novartis; and unpaid board member positions for the American Statistical Association, the Society for Clinical Trials, and the Frontier Science Foundation. Y. D. reports grants from Entasis and Shionogi, paid to his institution; consulting fees paid directly to him from Meiji Seika Pharma, Shionogi, Gilead, MSD, Chugai, and bioMérieux; speaker payments from MSD, Shionogi, Teijin Healthcare, Gilead, bioMérieux, and Eiken Chemical paid to him; and DSMB participation with FujiFilm. B. C. F. reports support from the US Veterans Affairs Merit Review Award 5I01 BX003741 and NIAID R01 AI127704, and is an attending at the US Department of Veterans Affairs (VA), Northport VA Medical Center, Northport, New York; contents of this review do not represent the views of VA or the US government. P. A. T. reports research support paid to institution from Sanofi, Moderna, and Shionogi as well as funding from Foundation Mérieux. H. F. C. reports participation on a Merck DSMB for molnupiravir paid directly to him, and stock ownership in Moderna and Merck. M. J. S. reports grants/contracts to his institution from Merck, Selux Diagnostics, SNIIPRBiome, and bioMérieux; consulting fees paid directly to him from Shionogi; and compensation for participation on a DSMB from AbbVie paid directly to him. V. G. F. reports grants to his institution from the NIH, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck, Medical Biosurfaces, Locus, Affinergy, ContraFect, Karius, Genentech, Regeneron, Basilea, and Janssen; royalties from UpToDate; personal fees from Novartis, Debiopharm, Genentech, Achaogen, Affinium, The Medicines Co, MedImmune, Bayer, Basilea, Affinergy, Janssen, ContraFect, Regeneron, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics, C3J, Armata, Valanbio, Akagera, Aridis, and Roche; editorial stipend from IDSA; pending patent for a host gene expression signature diagnostic for sepsis; and stock options with Valanbio and ArcBio. D. v. D. reports grants and contracts from the NIH, Merck, and Shinogi, paid to his institution, outside the published work; consultancy for Actavis, Tetraphase, Sanofi-Pasteur, MedImmune, Astellas, Merck, Allergan, T2Biosystems, Roche, Achaogen, Neumedicine, Shionogi, Pfizer, Entasis, Qpex, Wellspring, Karius, and Utility paid directly to him; honoraria from Pfizer; and an editor's stipend from the British Society for Antimicrobial Chemotherapy.

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