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Improved Phenotype-Based Definition for Identifying Carbapenemase Producers among Carbapenem-Resistant Enterobacteriaceae - Volume 21, Number 9—September 2015 - Emerging Infectious Disease journal - CDC


Improved Phenotype-Based Definition for Identifying Carbapenemase Producers among Carbapenem-Resistant Enterobacteriaceae - Volume 21, Number 9—September 2015 - Emerging Infectious Disease journal - CDC

Volume 21, Number 9—September 2015
Emerging Infections Program

Emerging Infections Program

Improved Phenotype-Based Definition for Identifying Carbapenemase Producers among Carbapenem-Resistant Enterobacteriaceae

Nora Chea, Sandra N. Bulens, Thiphasone Kongphet-Tran, Ruth Lynfield, Kristin M. Shaw, Paula Snippes Vagnone, Marion A. Kainer, Daniel B. Muleta, Lucy Wilson, Elisabeth Vaeth, Ghinwa Dumyati, Cathleen Concannon, Erin C. Phipps, Karissa Culbreath, Sarah J. Janelle, Wendy M. Bamberg, Alice Y. Guh, Brandi Limbago, and Alexander J. KallenComments to Author 
Author affiliations: Centers for Disease Control and Prevention, Atlanta, Georgia, USA (N. Chea, S.N. Bulens, T. Kongphet-Tran, A.Y. Guh, B. Limbago, A.J. Kallen)Minnesota Department of Health, St. Paul, Minnesota, USA (R. Lynfield, K.M. Shaw, P. Snippes Vagnone)Tennessee Department of Health, Nashville, Tennessee, USA (M.A Kainer, D.B. Muleta)Maryland Emerging Infections Program, Baltimore, Maryland, USA (L. Wilson, E. Vaeth);New York–Rochester Emerging Infections Program, Rochester, New York, USA (G. Dumyati, C. Concannon);University of Rochester Medical Center, Rochester (G. Dumyati, C. Concannon)University of New Mexico, Albuquerque, New Mexico, USA (E.C. Phipps, K. Culbreath)Colorado Department of Public Health and Environment, Denver, Colorado, USA (S.J. Janelle, W.M. Bamberg)


Preventing transmission of carbapenemase-producing, carbapenem-resistant Enterobacteriaceae (CP-CRE) is a public health priority. A phenotype-based definition that reliably identifies CP-CRE while minimizing misclassification of non–CP-CRE could help prevention efforts. To assess possible definitions, we evaluated enterobacterial isolates that had been tested and deemed nonsusceptible to >1 carbapenem at US Emerging Infections Program sites. We determined the number of non-CP isolates that met (false positives) and CP isolates that did not meet (false negatives) the Centers for Disease Control and Prevention CRE definition in use during our study: 30% (94/312) of CRE had carbapenemase genes, and 21% (14/67) of Klebsiella pneumoniae carbapenemase–producing Klebsiella isolates had been misclassified as non-CP. A new definition requiring resistance to 1 carbapenem rarely missed CP strains, but 55% of results were false positive; adding the modified Hodge test to the definition decreased false positives to 12%. This definition should be considered for use in carbapenemase-producing CRE surveillance and prevention.
Multidrug-resistant organisms are a major public health concern worldwide (14). Of particular concern has been the emergence of resistance to carbapenem antimicrobial drugs among Enterobacteriaceae (4,5). In the United States, the reported percentage of common health care–associated infections caused by carbapenem-nonsusceptible Enterobacteriaceae increased from 1.2% in 2001 to 4.2% in 2011 (4), and the greatest increase (≈10%) occurred among Klebsiella species (4).
Although carbapenem nonsusceptibility among Enterobacteriaceae can result from several mechanisms, much of the recent increase in carbapenem-resistant Enterobacteriaceae (CRE) in the United States is likely due to the spread of carbapenemase-producing strains, particularly Klebsiella species that produce Klebsiella pneumoniae carbapenemase (KPC) (3,4). In addition to KPC, several other carbapenemases have been identified in the United States: New Delhi metallo-β-lactamase (NDM), oxacillinase (OXA), Verona integron–encoded metallo-β-lactamase (VIM), and imipenemase (IMP) (5,6). These enzymes are encoded by mobile genetic elements that have the potential to spread between bacterial species. The uptake of these elements among different bacterial species could result in further increases in the prevalence of carbapenem-resistant or panresistant bacteria, or both, and if this occurs, treatment options in the United States would be limited (7). Since 2006, the Centers for Disease Control and Prevention (CDC) has identified >100 NDM-producing CRE in the United States, including those that caused 2 hospital-based outbreaks (8,9). In light of the elements described above, much of the effort to prevent further spread of CRE has targeted carbapenemase-producing CRE. However, these efforts have been hampered because many clinical laboratories do not routinely perform CRE resistance-mechanism testing, so they cannot differentiate carbapenemase-producing CRE from CRE that are carbapenem-nonsusceptible due to other mechanisms. In addition, resistance-mechanism testing is also not routinely recommended for clinical purposes by the Clinical and Laboratory Standards Institute (CLSI) (10).
A phenotype-based CRE definition (i.e., based on antimicrobial drug susceptibility pattern) that is specific for carbapenemase-producing strains has the potential to facilitate CRE prevention by allowing health care facilities to target these strains for the most aggressive interventions without the need to rely on resistance-mechanism testing. The pre-2015 CDC CRE surveillance definition—nonsusceptiblity to imipenem, meropenem, or doripenem, and resistance to all third-generation cephalosporins tested, as determined by using CLSI M100-S23 testing standards (11)—was originally designed to preferentially identify carbapenemase-producing CRE (9). However, because of the number of antimicrobial drugs included and the complexity of the third-generation cephalosporin restriction (resistance to all tested), this phenotype-based definition proved to be complicated and difficult to implement by health care facilities for both surveillance and infection control efforts. In addition, use of this definition led to the mistaken assumption that CRE that did not meet the definition did not warrant any additional infection control precautions beyond standard precautions (9).
The objective of this analysis was to identify a phenotype-based definition that accurately differentiates carbapenemase-producing CRE from non–carbapenemase-producing CRE on the basis of antimicrobial susceptibility patterns. To achieve this, we evaluated isolates collected through CDC’s Emerging Infections Program (EIP) CRE surveillance system (http://www.cdc.gov/hai/eip/mugsi.html).

Dr. Chea is an Epidemic Intelligence Service officer with the Division of Healthcare Quality Promotion at the CDC, Atlanta. His primary research interest is healthcare-associated infections.


We thank Kamile Rasheed and David Lonsway for their advice and Christine Lascols for confirmatory testing at CDC.


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Suggested citation for this article: Chea N, Bulens SN, Kongphet-Tran T, Lynfield R, Shaw KM, Vagnone PS, et al. Improved phenotype-based definition for identifying carbapenemase producers among carbapenem-resistant Enterobacteriaceae. Emerg Infect Dis. 2015 Sep [date cited].http://dx.doi.org/10.3201/eid2109.150198
DOI: 10.3201/eid2109.150198

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