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Improved phenotype-based definition for identifying carbapenemase producers among carbapenem-resistant Enterobacteriaceae.

Multidrug-resistant organisms are a major public health concern worldwide (1-4). 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-[beta]-lactamase (NDM), oxacillinase (OXA), Verona integron-encoded metallo-[beta]-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).

Methods

Inclusion Criteria and Data Collection

Isolates of Enterobacter spp., Escherichia coli, and Klebsiella spp. were collected from clinical laboratories that serve 6 EIP sites in the United States: Minnesota and Tennessee (both statewide); the 5-county Denver, Colorado, metropolitan area (Arapahoe, Adams, Denver, Douglas, and Jefferson Counties); the 4-county Baltimore, Maryland, metropolitan area (Baltimore City, Baltimore County, Howard County, and Carroll County); the Albuquerque, New Mexico, metropolitan area (Bernalillo County); and the Rochester, New York, metropolitan area (Monroe County). Four sites (Colorado, Maryland, New Mexico, and New York) submitted isolates from a preselected group of laboratories during March 10, 2013-January 30, 2014; two sites (Minnesota and Tennessee) submitted isolates received from statewide reporting starting January 1, 2011, and continuing through January 30, 2014. If >1 isolate of the same genus was obtained from a single patient, only 1 was included. Isolates that met the following 3 criteria were included: 1) evidence of nonsusceptibility (intermediate or resistant) to any carbapenem (imipenem, meropenem, doripenem, or ertapenem), as determined on the basis of susceptibility testing conducted at the local clinical laboratory by using 2013 CLSI breakpoints (11); 2) availability of susceptibility testing data from the reporting clinical laboratory for all antimicrobial drugs tested in the assessed phenotype-based definitions (Table 1); and 3) documentation of methods used for susceptibility testing.

Confirmatory Testing at CDC

Eligible Enterobacter spp., E. coli, and Klebsiella spp. isolates were sent to CDC for reference susceptibility testing (broth microdilution and Kirby-Bauer disk diffusion testing) for ertapenem, doripenem, imipenem, meropenem, 3 third-generation cephalosporins (ceftriaxone, cefotaxime, and ceftazidime), and cefepime (11). Three methods were used to evaluate each isolate for the presence of carbapenemases: the modified Hodge test (MHT), a broth microdilution screening test for metallo-[beta]-lactamases that compares the MIC of imipenem in the presence and absence of metal chelators (12), and PCR for the most common carbapenemases in the United States (i.e., [bla.sub.KPC], [bla.sub.NDM] and [bla.sub.OXA-48]). Isolates that were [bla.sub.NDM]-negative by PCR but [bla.sub.NDM]-positive by metallo-[beta]-lactamase screening were further evaluated by PCR for [bla.sub.VIM] and [bla.sub.IMP].

Analysis

Eleven phenotype-based definitions (Table 1) were initially evaluated: 1) nonsusceptible to any carbapenem, excluding ertapenem; 2) nonsusceptible to imipenem, meropenem, or doripenem and resistant to all third-generation cephalosporins tested (pre-2015 CDC CRE surveillance definition); 3) nonsusceptible to any carbapenem, excluding ertapenem, and resistant to any third-generation cephalosporins tested; 4) resistant to any carbapenem; 5) resistant to any carbapenem, excluding ertapenem; 6) resistant to any carbapenem and resistant to all third-generation cephalosporins tested; 7) resistant to any carbapenem and resistant to any third-generation cephalosporin tested; 8) nonsusceptible to at least 2 carbapenems (ertapenem resistant, if tested); 9) nonsusceptible to any carbapenem (ertapenem resistant, if tested) and resistant to cefepime; 10) resistant to any carbapenem and resistant to cefepime; and 11) nonsusceptible to any carbapenem, excluding ertapenem, and resistant to cefepime. All susceptibility interpretations were determined on the basis of the 2013 CLSI breakpoints (11). With the exception of CRE that are OXA-48-like producers, most carbapenemase producers are multidrug resistant and should be resistant to third-generation cephalosporins. Thus, in an attempt to improve detection of carbapenemase-producing CRE, we included third-generation cephalosporins in certain definitions. Similarly, we added cefepime to certain definitions to ascertain if it might help discriminate between AmpC-producing and carbapenemase-producing CRE.

For each of the 11 phenotype-based definitions, we performed 4 calculations based on the clinical laboratory-determined susceptibility results for carbapenem-nonsusceptible isolates. The calculations determined the number and percentage of 1) carbapenemase-producing isolates that screened positive (true positives [TP]); 2) carbapenemase-producing isolates identified that screened negative (selected false negatives [sFNs]); 3) non-carbapenemase-producing isolates that screened positive (false positives [FPs]); and 4) non-carbapenemase-producing isolates identified that screened negative (selected true negative [sTN]). The denominator for each of the calculations was the number of isolates for which the definitions could be applied on the basis of results at the clinical laboratory. Because we limited our isolates to those with nonsusceptibility to a carbapenem and could only calculate sFN and sTN screening results, we could not determine the specificity, sensitivity, or negative predictive value of a definition. Three of the 11 definitions were further stratified by EIP site and organism tested to evaluate differences in their FP and sFN results by geographic region and by genus. The 3 definitions were the one that obtained the lowest number of sFNs, the one that obtained the lowest number of FPs among definitions with potentially acceptable levels of sFNs (defined as <10%), and the pre-2015 CDC CRE surveillance definition. Analysis was limited to EIP sites that submitted >50 isolates. We performed 2-step testing by adding MHT results to the susceptibility results for the isolates meeting the definition with the lowest number of sFNs to determine if the results of the MHT affected the the percentage of isolates classified as FP and sFN.

Results

A total of 312 isolates were included in this evaluation; the number from each EIP site and the number for each included genus are shown in Table 2. A carbapenemase gene was identified in 94 (30%) of the 312 isolates. Seventy-two (65%) Klebsiella spp. isolates had a carbapenemase gene, of which 67 (93%) were KPC and 5 (7%) were NDM. Of all Enterobacter spp. and E. coli isolates, 14 (14%) and 8 (8%), respectively, had a carbapenemase gene, and all were KPC. The percentage of carbapenemase-producing CRE at the various sites was 73% in Maryland (40 [93%] KPC, 3 [7%] NDM); 30% in Minnesota (31 [94%] KPC, 2 [6%] NDM); 20% in Tennessee (13 [100%] KPC); 6% in New York (3 [100%] KPC); 7% in New Mexico (1 [100%] KPC); and 0 in Colorado.

The numbers and percentages of FPs and sFNs obtained with each of the 11 evaluated definitions are shown in Table 3. The percentage of FPs and sFNs ranged from 5.5% to 55.0% and 0.7% to 27.7%, respectively. The 3 phenotype-based definitions meeting the requirements for the prespecified stratified analysis by site and genus were the one with the lowest number of sFNs (definition 4, resistant to any carbapenem); the one with the lowest number of FPs among definitions with potentially acceptable levels of sFNs, defined as <10% (definition 5, resistant to any carbapenem without ertapenem); and the pre-2015 CDC CRE surveillance definition (definition 2).

The numbers and percentages of FPs and sFNs obtained by using these 3 definitions are shown by EIP site in Table 4. The percentage of FPs was highest in Minnesota and Tennessee, and the percentage of sFNs was highest in Tennessee. The number and percentage of FPs and sFNs obtained by using the same 3 definitions are shown by organism tested in Table 5. The highest percentage of sFNs obtained by using definitions 2 and 5 were among Klebsiella spp.; overall, sFNs were generally lower for E. coli and Enterobacter spp. Of note, definition 4 had the narrowest variability in the percentage of sFNs across all sites (range 0%-1.5%) and among the 3 enterobacterial organisms (range 0%- 1.1 %). Of the 67 KPC-producing Klebsiella spp., 14 (21%), 1 (1%), and 14 (21%) did not meet definitions 2, 4, and 5, respectively. Of the 14 KPC-producing Klebsiella spp. isolates that did not meet definitions 2 and 5, a total of 12 (86%) were susceptible to all carbapenems tested except ertapenem. All 5 NDM-producing Klebsiella spp. met the 3 definitions.

A comparison of the MHT and PCR results by enterobacterial organism and carbapenem used in the MHT is shown in Table 6. The MHT showed no sFNs for all 3 organisms and a small number of FPs for Klebsiella spp. (3%) and E. coli (3%-4%); however, the MHT misclassified 31%-34% of non-carbapenemase-producing Enterobacter spp. as carbapenemase producers. The effect from adding the MHT to definition 4 is shown in Tables 4 and 5. Addition of the MHT to definition 4 decreased the overall percentage of FPs from 55% to 12%, but the percentage of sFNs remained at 0.7%. FPs were reduced substantially for Klebsiella spp. (from 27.9% to 2.7%) and E. coli (74.5% to 4%) but remained higher for Enterobacter spp. (29%).

Discussion

In this evaluation, no phenotype-based definition identified all carbapenemase-producing CRE without also capturing a substantial number of non-carbapenemase-producing CRE. The percentages of FPs and sFNs varied by enterobacterial organism and by EIP site, likely due to the underlying variation in the prevalence of carbapenemase-producing CRE in different areas and among different Enterobacteriaceae. In this sample of isolates, the pre-2015 CDC CRE surveillance definition misclassified nearly 13% of carbapenem-nonsusceptible Klebsiella spp. isolates and 21% of KPC-producing Klebsiella spp. isolates as non-carbapenemase producing. In light of this finding, a phenotype-based definition that captures all (or nearly all) carbapenemase-producing CRE should be considered for surveillance and prevention. However, our data demonstrate that alternative definitions that accomplish this also increase the number of FPs and thus have the potential to increase the amount of work and the cost associated with CRE surveillance and prevention efforts.

Current efforts to control CRE in the United States have used infection prevention strategies targeted at carbapenemase-producing strains; however, most clinical laboratories do not routinely differentiate carbapenemase-producing from non-carbapenemase-producing strains. Molecular detection of genes encoding carbapenemases is the reference standard for identifying carbapenemase-producing CRE, but this testing requires substantial expertise and expense. More readily available tests, like the MHT, could likely be performed in most clinical microbiology laboratories, but they require additional technician time and reagents, which creates a burden on laboratory resources and therefore limits their routine use. In addition, the MHT might falsely identify NDM-producing strains as non-carbapenemase-producing CRE and might falsely identify non-carbapenemase-producing Enterobacter spp. as carbapenemase-producing CRE (13). Another carbapenemase detection test, the Carba-NP, has good performance characteristics and may be a viable alternative; however, it is not yet widely used (13-16). Because of the limited availability and technical challenges associated with resistance-mechanism testing for CRE, a definition for CRE that increases detection of carbapenemase-producing strains while reasonably limiting the number of non-carbapenemase-producing strains identified would aid surveil lance and infection control efforts until resistance-mechanism-based testing becomes more routinely available.

Our results show that the use of definition 4 (resistant to any carbapenem) obtained one of the lowest percentages of sFN results. In addition, between EIP sites and between the 3 enterobacterial organisms, there was little variability in the percentage of isolates with sFN results, suggesting the results may be reflective of what other hospitals in the United States might experience when using this CRE definition to capture carbapenemase-producing CRE isolates. In January 2015, CDC modified its surveillance definition for CRE. The change was made partly because of the results of findings from this evaluation but also as an effort to simplify the CRE surveillance definition so that it can be applied more easily. The new definition (resistant to imipenem, meropenem, doripenem, or ertapenem or documentation that the isolate possesses a carbapenemase) is to be used with current CLSI breakpoints (10). To further reduce the number of non-carbapenemase-producing CRE strains falsely identified as carbapenemase-producing CRE, health care facilities could consider adding resistance-mechanism testing for isolates that meet this definition. Such testing may be particularly helpful in areas with a low prevalence of CRE and with organisms that are less likely to produce carbapenemases (e.g., E. coli and Enterobacter spp.).

This evaluation has several limitations. First, our testing collection consisted of a relatively small number of isolates from a limited number of sites, and because strain typing was not performed on any of the isolates included in this analysis, we cannot exclude the possibility that some of these isolates might have been related to each other. However, this evaluation did include isolates from diverse locations in the United States that represent areas with low and relatively high prevalences of CRE. Second, isolates from only 3 genera were included, limiting the generalizability of any conclusions beyond these organisms. Last, our sample included mostly KPC-producing CRE among the carbapenemase-producing strains. These results may not be applicable to other emerging carbapenemases, specifically NDM and OXA. However, current epidemiology suggests that KPC remains the most common carbapenemase in the United States.

In conclusion, the pre-2015 CDC CRE surveillance definition failed to identify some carbapenemase-producing strains. A definition that includes only resistance to any 1 of the 4 approved carbapenems is simpler and misses fewer carbapenemase-producing strains, but at the cost of increasing FPs. The addition of the MHT to this definition further limits FPs; however, this testing is not routinely used in the United States. In general, all organisms that are nonsusceptible to a carbapenem are potentially multidrug-resistant and, at minimum, warrant the use of interventions such as contact precautions to minimize transmission. Health care facilities could choose to reserve more aggressive interventions, such as screening of contacts and patient cohorting, for patients with isolates that meet this new definition, which appears to more completely detect carbapenemase-producing CRE. Health care facilities wishing to limit the work and expense associated with more aggressive interventions could perform resistance-mechanism testing on isolates meeting this new definition and apply interventions only when the isolates are confirmed to produce carbapenemase.

Address for correspondence: Alexander J. Kallen, Centers for Disease Control and Prevention, 1600 Clifton Rd NE, Mailstop A31, Atlanta, GA 30329-4027, USA; email: ffp0@cdc.gov

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, Alexander J. Kallen

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)

DOI: http://dx.doi.org/10.3201/eid2109.150198

Acknowledgments

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

References

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Table 1. Summary of 11 phenotype-based definitions evaluated
for reliability in identifying carbapenemase producers among
carbapenem-resistant Enterobacteriaceae, United States,
January 1, 2011-January 30, 2014 *

Antimicrobial included                  Study     Definition ([dagger])
                                      inclusion
                                      criteria

                                                  1    2    3    4

Any carbapenem ([double dagger])         NS                      R
Any carbapenem (without ertapenem)                NS   NS   NS
[greater than or equal to] 2
  carbapenems ([double dagger])
All third-generation                                   R
  cephalosporins tested
Any third-generation                                        R
  cephalosporins tested
Cefepime

Antimicrobial included                Definition ([dagger])

                                      5   6   7         8

Any carbapenem ([double dagger])          R   R
Any carbapenem (without ertapenem)    R
[greater than or equal to] 2                      NS ([section])
  carbapenems ([double dagger])
All third-generation                      R
  cephalosporins tested
Any third-generation                          R
  cephalosporins tested
Cefepime

Antimicrobial included                Definition ([dagger])

                                            9          10   11

Any carbapenem ([double dagger])      NS ([section])   R
Any carbapenem (without ertapenem)                          NS
[greater than or equal to] 2
  carbapenems ([double dagger])
All third-generation
  cephalosporins tested
Any third-generation
  cephalosporins tested
Cefepime                                    R          R    R

* NS, nonsusceptible; R, resistant. Blank cells mean not included
in the definition.

([dagger]) Interpretation based on Clinical and Laboratory Standards
Institute breakpoints (M100-S23) (7 7). Definitions: 1, nonsusceptible
to any carbapenem, excluding ertapenem; 2, nonsusceptible to any
carbapenem, excluding ertapenem, and resistant to all third-generation
cephalosporins tested (pre-2015 Centers for Disease Control and
Prevention carbapenem-resistant Enterobacteriaceae surveillance
definition); 3, nonsusceptible to any carbapenem, excluding ertapenem,
and resistant to any third-generation cephalosporins tested; 4,
resistant to any carbapenem; 5, resistant to any carbapenem, excluding
ertapenem; 6, resistant to any carbapenem and resistant to all
third-generation cephalosporins tested; 7, resistant to any carbapenem
and resistant to any third-generation cephalosporin tested; 8,
nonsusceptible to at least 2 carbapenems (ertapenem resistant, if
tested); 9, nonsusceptible to any carbapenem (ertapenem resistant,
if tested) and resistant to cefepime; 10, resistant to any carbapenem
and resistant to cefepime; and 11, nonsusceptible to any carbapenem,
excluding ertapenem, and resistant to cefepime.

([double dagger]) Ertapenem, doripenem, imipenem, and meropenem.

([section]) If ertapenem used in the definition, isolate would need
to be resistant (i.e., MIC [greater than or equal to] 2 [micro]g/mL).

Table 2. Isolates used in a study evaluating phenotype-based
definitions for reliability in identifying carbapenemase
producers among carbapenem-resistant enterobacterial isolates
from 6 US Emerging Infections Program sites, January 1,
2011-January 30, 2014

Site                             No. (%) isolates

              Klebsiella     Enterobacter    Escherichia    Total no.
             spp., n = 111   spp., n = 103   coli, n = 98   isolates,
                                                             N = 312

Minnesota       30 (27)         63 (56)        19 (17)         112
Tennessee       17 (25)         11 (16)        41 (59)         69
Maryland        48 (81)            0           11 (19)         59
New York        11 (20)         20 (38)        22 (42)         53
New Mexico      5 (33)          6 (40)          4 (27)         15
Colorado           0            3 (75)          1 (25)          4

Table 3. False-positive and selected false-negative results
in a study evaluating phenotype-based definitions for
reliability in identifying carbapenemase producers among
carbapenem-resistant enterobacterial isolates from 6 US
Emerging Infections Program sites, January 1, 2011-January
30, 2014

Result                 No. isolates/no. tested (%),
                       by definition no., N = 307 *

                1        2        3         4        5         6

False-       117/307   82/307   91/307   169/307   57/307   146/307
  positive   (38.1)    (26.7)   (29.6)   (55.0)    (18.6)   (47.6)
Selected     12/307    15/307   13/307    2/307    17/307    7/307
  false-      (3.9)    (4.9)    (4.2)     (0.7)    (5.5)     (2.3)
  negative

Result              No. isolates/no. tested (%),
                    by definition no., N = 307 *

                7        8        9        10       11

False-       153/307   60/307   37/307   34/307   17/307
  positive   (49.8)    (19.5)   (12.1)   (11.1)   (5.5)
Selected      4/307    27/307   85/307   85/307   85/307
  false-      (1.3)    (8.8)    (27.7)   (27.7)   (27.7)
  negative

* False-positive isolates are those meeting the definition
but not found to produce a carbapenemase. Selected
false-negative isolates were selected on the basis of
nonsuceptibility to [greater than or equal to]1 carbapenem
not meeting the definition but found to produce a
carbapenemase. Definitions: 1, nonsusceptible to any
carbapenem, excluding ertapenem; 2, nonsusceptible to any
carbapenem, excluding ertapenem, and resistant to all third-generation
cephalosporins tested (pre-2015 Centers for
Disease Control and Prevention carbapenem-resistant
Enterobacteriaceae surveillance definition); 3,
nonsusceptible to any carbapenem, excluding ertapenem, and
resistant to any third-generation cephalosporins tested; 4,
resistant to any carbapenem; 5, resistant to any carbapenem,
excluding ertapenem; 6, resistant to any carbapenem and
resistant to all third-generation cephalosporins tested; 7,
resistant to any carbapenem and resistant to any
third-generation cephalosporin tested; 8, nonsusceptible to at
least 2 carbapenems (ertapenem resistant, if tested); 9,
nonsusceptible to any carbapenem (ertapenem resistant, if
tested) and resistant to cefepime; 10, resistant to any
carbapenem and resistant to cefepime; and 11, nonsusceptible
to any carbapenem, excluding ertapenem, and resistant to
cefepime.

Table 4. Results, by study site, for select phenotype-based
definitions used to identify carbapenemase producers among 307
carbapenem-resistant enterobacterial isolates from 4 US EIP,
Emerging Infections Program sites, January 1, 2011-January 30,
2014 *

Site        No. isolates/no. tested (%), by definition no. ([dagger])

                 2 ([double dagger])             4 ([section])

                 FP             sFN            FP             sFN

Minnesota   51/111 (45.9)   3/111 (2.7)   55/111 (49.5)   1/111 (0.9)
Tennessee   17/65 (26.2)    4/65 (6.2)    50/65 (76.9)    1/65 (1.5)
Maryland     6/59 (10.2)    5/59 (8.5)    16/59 (27.1)       0/59
New York     4/53 (7.5)     2/53 (3.8)    31/53 (58.5)       0/53

Site        No. isolates/no. tested (%), by definition no. ([dagger])

                  5 ([paragraph])               4 plus MHT (#)

                 FP             sFN            FP             sFN

Minnesota   25/111 (22.5)   5/111 (4.5)   23/111 (20.7)   1/111 (0.9)
Tennessee   18/65 (27.7)    4/65 (6.2)     3/65 (4.6)     1/65 (1.5)
Maryland     3/59 (5.1)     6/59 (10.2)    3/59 (5.1)        0/59
New York     8/53 (15.1)    1/53 (1.9)     3/53 (5.7)        0/53

* FP, false positive; MHT, the modified Hodge test; sFN, selected
false negative.

([dagger]) False-positive isolates are those meeting the definition
but not found to produce a carbapenemase. Selected false-negative
isolates were selected on the basis of nonsuceptibility to [greater
than or equal to] 1 carbapenem not meeting the definition but found
to produce a carbapenemase.

([double dagger]) Definition 2 nonsusceptible to any carbapenem,
excluding ertapenem, and resistant to all third-generation
cephalosporins tested (pre-2015 Centers for Disease Control and
Prevention carbapenem-resistant Enterobacteriaceae surveillance
definition).

([section]) Definition 4, resistant to any carbapenem. This
definition obtained the lowest number of selected false-negatives.

([paragraph]) Definition 5, resistant to any carbapenem, excluding
ertapenem. This definition obtained the lowest number of
false-positives among definitions with selected false-negatives of
[less than or equal to] 10%.

(#) Definition 4 (resistant to any carbapenem) plus MHT (i.e.,
2-step testing).

Table 5. Results, by organism tested, for select phenotype-based
definitions used to identify carbapenemase producers among 307
carbapenem-resistant enterobacterial isolates from 6 US Emerging
Infections Program sites, January 1, 2011-January 30, 2014 *

Organism       Definition no., result, no.
               isolates/no. total (%) ([dagger])

               2 ([double dagger])         4 ([section])

                False-       Selected       False-       Selected
               positive   false-negative   positive   false-negative

Klebsiella      15/111    14/111 (12.6)     31/111     1/111 (0.9)
  spp.          (13.5)                      (27.9)
Enterobacter    42/102        0/102         68/102        0/102
  spp.          (41.2)                      (66.7)
Escherichia     25/94       1/94 (1.1)      70/94       1/94 (1.1)
  coli          (26.6)                      (74.5)

Organism       Definition no., result, no.
               isolates/no. total (%) ([dagger])

               5 ([paragraph])             4 plus MHT (#)

                False-       Selected       False-       Selected
               positive   false-negative   positive   false-negative

Klebsiella      11/111    14/111 (12.6)     3/111      1/111 (0.9)
  spp.          (9.9)                       (2.7)
Enterobacter    26/102        0/102         30/102        0/102
  spp.          (25.5)                      (29.4)
Escherichia     20/94       3/94 (3.2)       3/94       1/94 (1.1)
  coli          (21.3)                      (3.2)

* MHT, the modified Hodge test.

([dagger]) False-positive isolates are those meeting the definition
but not found to produce a carbapenemase. Selected false-negative
isolates were selected on the basis of nonsuceptibility to [greater
than or equal to] 1 carbapenem not meeting the definition but found
to produce a carbapenemase.

([double dagger]) Definition 2 nonsusceptible to any carbapenem,
excluding ertapenem, and resistant to all third-generation
cephalosporins tested (pre-2015 Centers for Disease Control and
Prevention carbapenem-resistant Enterobacteriaceae surveillance
definition).

([section]) Definition 4, resistant to any carbapenem. This
definition obtained the lowest number of selected false-negatives.

([paragraph]) Definition 5, resistant to any carbapenem, excluding
ertapenem. This definition obtained the lowest number of
false-positives among definitions with selected false-negatives
of [less than or equal to] 10%.

(#) Definition 4 (resistant to any carbapenem) plus MHT (i.e.,
2-step testing).

Table 6. Results for modified Hodge test evaluation
of 312 enterobacterial isolates from 6 US Emerging
Infections Program sites, January 1,2011-January
30, 2014

Organism,         False-positive   Selected false-negative
carbapenem used     results, %             results

Klebsiella spp.

  Meropenem            2.7                    0
  Ertapenem            2.7                    0

Enterobacter spp.

  Meropenem             31                    0
  Ertapenem             34                    0

Escherichia coli

  Meropenem             3                     0
  Ertapenem             4                     0
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Author:Chea, Nora; Bulens, Sandra N.; Kongphet-Tran, Thiphasone; Lynfield, Ruth; Shaw, Kristin M.; Vagnone,
Publication:Emerging Infectious Diseases
Article Type:Report
Date:Sep 1, 2015
Words:4942
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