Carbapenem-resistant Enterobacterales (CRE) are a growing public health concern due to resistance to multiple antibiotics and potential to cause health care-associated infections with high mortality. Carbapenemase-producing CRE are of particular concern given that carbapenemase-encoding genes often are located on mobile genetic elements that may spread between different organisms and species. In this study, we performed phenotypic and genotypic characterization of CRE collected at eight U.S. sites participating in active population- and laboratory-based surveillance of carbapenem-resistant organisms. Among 421 CRE tested, the majority were isolated from urine (n = 349, 83%).
Klebsiella pneumoniae
was the most common organism (n = 265, 63%), followed by Enterobacter cloacae complex (n = 77, 18%) and Escherichia coli (n = 50, 12%). Of 419 isolates analyzed by whole genome sequencing, 307 (73%) harbored a carbapenemase gene; variants of blaKPC predominated (n = 299, 97%). The occurrence of carbapenemase-producing K. pneumoniae, E. cloacae complex, and E. coli varied by region; the predominant sequence type within each genus was ST258, ST171, and ST131, respectively. None of the carbapenemase-producing CRE isolates displayed resistance to all antimicrobials tested; susceptibility to amikacin and tigecycline was generally retained.
BonomoR.A., BurdE.M, ConlyJ., et al.2018. Carbapenemase-producing organisms: a global scourge. Clin. Infect. Dis. 66:1290–1297.
3.
FalagasM.E., TansarliG.S, KarageorgopoulosD.E, and VardakasK.Z.. 2014. Deaths attributable to carbapenem-resistant Enterobacteriaceae infections. Emerg. Infect. Dis. 20:1170–1175.
4.
KohlerP.P., VollingC., GreenK., UlerykE.M, ShahP.S, McGeerA.. 2017. Carbapenem resistance, initial antibiotic therapy, and mortality in Klebsiella pneumoniae bacteremia: a systematic review and meta-analysis. Infect. Control Hosp. Epidemiol. 38:1319–1328.
5.
van LoonK., Voor In ‘t HoltA.F, and VosM.C.. 2018. A systematic review and meta-analyses of the clinical epidemiology of carbapenem-resistant Enterobacteriaceae. Antimicrob. Agents Chemother. 62:e01730-17.
6.
BradfordP.A., BratuS., UrbanC., et al.2004. Emergence of carbapenem-resistant Klebsiella species possessing the class A carbapenem-hydrolyzing KPC-2 and inhibitor-resistant TEM-30 beta-lactamases in New York City. Clin. Infect. Dis. 39:55–60.
7.
KanamoriH., ParobekC.M, JulianoJ.J, et al.2017. A prolonged outbreak of KPC-3-producing Enterobacter cloacae and Klebsiella pneumoniae driven by multiple mechanisms of resistance transmission at a Large Academic Burn Center. Antimicrob. Agents Chemother. 61:e01516-16.
8.
SnitkinE.S., ZelaznyA.M, ThomasP.J, et al.2012. Tracking a hospital outbreak of carbapenem-resistant Klebsiella pneumoniae with whole-genome sequencing. Sci. Transl. Med. 4:148ra116.
9.
YigitH., QueenanA.M, AndersonG.J, et al.2001. Novel carbapenem-hydrolyzing beta-lactamase, KPC-1, from a carbapenem-resistant strain of Klebsiella pneumoniae. Antimicrob. Agents Chemother. 45:1151–1161.
10.
EpsteinL., HunterJ.C, ArwadyM.A, et al.2014. New Delhi metallo-beta-lactamase-producing carbapenem-resistant Escherichia coli associated with exposure to duodenoscopes. JAMA, 312:1447–1455.
11.
LutgringJ.D., ZhuW., de ManT.J.B, et al.2018. Phenotypic and genotypic characterization of Enterobacteriaceae producing oxacillinase-48-like carbapenemases, United States. Emerg. Infect. Dis. 24:700–709.
12.
GuhA.Y., BulensS.N, MuY., et al.2015. Epidemiology of carbapenem-resistant Enterobacteriaceae in 7 US communities, 2012–2013. JAMA, 314:1479–1487.
13.
Clinical and Laboratory Standards Institute. 2018. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; 11th ed. CLSI Standard M07. Wayne, PA: Clinical and Laboratory Standards Institute.
14.
Clinical and Laboratory Standards Institute. 2021. Performance Standards for Antimicrobial Susceptibility Testing. 31st ed. CLSI Supplement M100. Clinical and Laboratory Standards Institute.
15.
CheaN., BulensS.N, Kongphet-TranT., et al.2015. Improved phenotype-based definition for identifying carbapenemase producers among carbapenem-resistant Enterobacteriaceae. Emerg. Infect. Dis. 21:1611–1616.
16.
BolgerA.M., LohseM., and UsadelB.. 2014. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics, 30:2114–2120.
17.
BankevichA., NurkS., AntipovD., et al.2012. SPAdes: a new genome assembly algorithm and its applications to single-cell sequencing. J. Comput. Biol. 19:455–477.
18.
InouyeM., DashnowH., RavenL.A, et al.2014. SRST2: rapid genomic surveillance for public health and hospital microbiology labs. Genome Med. 6:90.
19.
GuptaS.K., PadmanabhanB.R, DieneS.M, et al.2014. ARG-ANNOT, a new bioinformatic tool to discover antibiotic resistance genes in bacterial genomes. Antimicrob. Agents Chemother. 58:212–220.
20.
ZankariE., HasmanH., CosentinoS., et al.2012. Identification of acquired antimicrobial resistance genes. J. Antimicrob. Chemother. 67:2640–2644.
21.
GrundmannH., GlasnerC., AlbigerB., et al.2017. Occurrence of carbapenemase-producing Klebsiella pneumoniae and Escherichia coli in the European survey of carbapenemase-producing Enterobacteriaceae (EuSCAPE): a prospective, multinational study. Lancet. Infect. Dis. 17:153–163.S
22.
KitchelB., RasheedJ.K, PatelJ.B, et al.2009. Molecular epidemiology of KPC-producing Klebsiella pneumoniae isolates in the United States: clonal expansion of multilocus sequence type 258. Antimicrob. Agents Chemother. 53:3365–3370.
23.
AhnC., SyedA., HuF., O'HaraJ.A, RiveraJ.I, and DoiY.. 2014. Microbiological features of KPC-producing Enterobacter isolates identified in a U.S. hospital system. Diagn. Microbiol. Infect. Dis. 80:154–158.
24.
Gomez-SimmondsA., AnnavajhalaM.K, WangZ., et al.2018. Genomic and geographic context for the evolution of high-risk carbapenem-resistant Enterobacter cloacae complex clones ST171 and ST78. MBio, 9:e00542-18.
25.
PecoraN.D., LiN., AllardM., et al.2015. Genomically informed surveillance for carbapenem-resistant Enterobacteriaceae in a health care system. MBio, 6:e01030.
26.
HargreavesM.L., ShawK.M, DobbinsG., et al.2015. Clonal dissemination of Enterobacter cloacae harboring blaKPC-3 in the upper Midwestern United States. Antimicrob. Agents Chemother. 59:7723–7734.
27.
Nicolas-ChanoineM.H., BlancoJ., Leflon-GuiboutV., et al.2008. Intercontinental emergence of Escherichia coli clone O25:H4-ST131 producing CTX-M-15. J. Antimicrob. Chemother. 61:273–281.
28.
PettyN.K., Ben ZakourN.L, Stanton-CookM., et al. 2014. Global dissemination of a multidrug resistant Escherichia coli clone. Proc. Natl. Acad. Sci. U S A. 111:5694–5699.
29.
Nicolas-ChanoineM.H., BertrandX., and MadecJ.Y.. 2014. Escherichia coli ST131, an intriguing clonal group. Clin. Microbiol. Rev. 27:543–574.
30.
PeiranoG., BradfordP.A, KazmierczakK.M, et al.2014. Global incidence of carbapenemase-producing Escherichia coli ST131. Emerg. Infect. Dis. 20:1928–1931.
31.
BeaubienA.R., OrmsbyE., BayneA., et al.1991. Evidence that amikacin ototoxicity is related to total perilymph area under the concentration-time curve regardless of concentration. Antimicrob. Agents Chemother. 35:1070–1074.
32.
LimL.M., LyN., AndersonD., et al.2010. Resurgence of colistin: a review of resistance, toxicity, pharmacodynamics, and dosing. Pharmacotherapy, 30:1279–1291.
33.
AnthonyK.B., FishmanN.O, LinkinD.R, GasinkL.B, EdelsteinP.H, and LautenbachE.. 2008. Clinical and microbiological outcomes of serious infections with multidrug-resistant gram-negative organisms treated with tigecycline. Clin. Infect. Dis. 46:567–570.
34.
PrasadP., SunJ., DannerR.L, and NatansonC.. 2012. Excess deaths associated with tigecycline after approval based on noninferiority trials. Clin. Infect. Dis. 54:1699–1709.
HaydenM.K., LinM.Y, LolansK., et al.2015. Prevention of colonization and infection by Klebsiella pneumoniae carbapenemase-producing enterobacteriaceae in long-term acute-care hospitals. Clin. Infect. Dis. 60:1153–1161.
37.
Munoz-PriceL.S., HaydenM.K, LolansK., et al.2010. Successful control of an outbreak of Klebsiella pneumoniae carbapenemase-producing K. pneumoniae at a long-term acute care hospital. Infect. Control. Hosp. Epidemiol. 31:341–347.
38.
HumphriesR.M., HindlerJ.A, EpsonE., et al.2018. Carbapenem-resistant Enterobacteriaceae detection practices in California: what are we missing? Clin. Infect. Dis. 66:1061–1067.
39.
LutgringJ.D., and LimbagoB.M.. 2016. The problem of carbapenemase-producing-carbapenem-resistant-Enterobacteriaceae detection. J. Clin. Microbiol. 54:529–534.
40.
PierceV.M., SimnerP.J, LonswayD.R, et al.2017. Modified carbapenem inactivation method for phenotypic detection of carbapenemase production among Enterobacteriaceae. J. Clin. Microbiol. 55:2321–2333.
41.
VasooS., CunninghamS.A, KohnerP.C, et al.2013. Comparison of a novel, rapid chromogenic biochemical assay, the Carba NP test, with the modified Hodge test for detection of carbapenemase-producing Gram-negative bacilli. J. Clin. Microbiol. 51:3097–3101.
42.
PogueJ.M., HeilE.L, LephartP., et al.2018. An antibiotic stewardship program blueprint for optimizing verigene BC-GN within an institution: a tale of two cities. Antimicrob. Agents Chemother. 62:e02538-17.
43.
SouthernT.R., VanSchooneveldT.C, BannisterD.L, et al.2015. Implementation and performance of the BioFire FilmArray(R) Blood Culture Identification panel with antimicrobial treatment recommendations for bloodstream infections at a midwestern academic tertiary hospital. Diagn. Microbiol. Infect. Dis. 81:96–101.
44.
TatoM., Ruiz-GarbajosaP., TraczewskiM., et al.2016. Multisite evaluation of cepheid Xpert Carba-R assay for detection of carbapenemase-producing organisms in rectal swabs. J. Clin. Microbiol. 54:1814–1819.
45.
WrightH., BonomoR.A, and PatersonD.L.. 2017. New agents for the treatment of infections with Gram-negative bacteria: restoring the miracle or false dawn? Clin. Microbiol. Infect. 23:704–712.
46.
NelsonK., HemarajataP., SunD., et al.2017. Resistance to ceftazidime-avibactam is due to transposition of KPC in a porin-deficient strain of Klebsiella pneumoniae with increased efflux activity. Antimicrob. Agents Chemother. 61:e00989-17.
47.
WangY., WangJ., WangR., and CaiY.. 2020. Resistance to ceftazidime-avibactam and underlying mechanisms. J. Glob. Antimicrob Resist. 22:18–27.
48.
GaibaniP., LombardoD., BussiniL., et al.2021. Epidemiology of meropenem/vaborbactam resistance in KPC-producing Klebsiella pneumoniae causing bloodstream infections in Northern Italy, 2018. Antibiotics (Basel). 10:536.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
