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Journal of Clinical Microbiology, December 1999, p. 4065-4070, Vol. 37, No. 12
0095-1137/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Detection and Reporting of Organisms Producing Extended-Spectrum
-Lactamases: Survey of Laboratories in Connecticut
Fred C.
Tenover,1,*
M. Jasmine
Mohammed,1
Timothy S.
Gorton,2 and
Zygmunt
F.
Dembek3
Hospital Infections Program, Centers for
Disease Control and Prevention, Atlanta, Georgia
303331; University of Connecticut,
Department of Pathobiology, Storrs, Connecticut
062692; and Epidemiology Program,
Connecticut Department of Public Health, Hartford, Connecticut
06134-03083
Received 30 June 1999/Returned for modification 5 August
1999/Accepted 1 September 1999
 |
ABSTRACT |
Extended-spectrum 
-lactamases (ESBLs) are enzymes produced in
some gram-negative bacilli that mediate resistance to extended-spectrum cephalosporins and aztreonam. They are most common in
Klebsiella spp. and Escherichia coli but are
present in a variety of Enterobacteriaceae. Resistance
mediated by these enzymes can be difficult to detect depending on the
antimicrobial agents tested. AmpC -lactamases are related to the
chromosomal enzymes of Enterobacter and
Citrobacter spp. and also mediate resistance to
extended-spectrum cephalosporins and aztreonam in addition to
cephamycins, such as cefoxitin. Unlike ESBLs, however, AmpC
-lactamases are not inhibited by clavulanic acid or other similar
compounds. To assess the abilities of various antimicrobial
susceptibility testing methods to detect ESBLs, we sent three
ESBL-producing organisms, one AmpC-producing organism, and a control
strain that was susceptible to extended-spectrum cephalosporins to 38 laboratories in Connecticut for testing. Eight (21.0%) of 38 labs
failed to detect extended-spectrum cephalosporin or aztreonam
resistance in any of the ESBL- or AmpC-producing isolates. Errors were
encountered with both automated and disk diffusion methods. Conversely,
seven (18.4%) labs categorized at least some of the four resistant
isolates as potential ESBL producers and reported the results with the
extended-spectrum cephalosporins and aztreonam as resistant as
suggested by current National Committee for Clinical Laboratory
Standards (NCCLS) guidelines. The percentage of laboratories that
failed to detect resistance in the ESBL or AmpC isolates ranged from
23.7 to 31.6% depending on the type of enzyme present in the test
organism. This survey suggests that many laboratories have difficulty
detecting resistance in ESBL and AmpC-producing organisms and may be
unaware of the NCCLS guidelines on modifying susceptibility testing
reports for ESBL-producing strains.
| |
INTRODUCTION |
Extended-spectrum -lactamases
(ESBLs) are enzymes that mediate resistance to extended-spectrum
cephalosporins, such as cefotaxime, ceftriaxone, and ceftazidime, and
the monobactam aztreonam (10, 13, 15). Such enzymes are most
commonly found in Klebsiella pneumoniae and
Escherichia coli, but they have also been detected in
Klebsiella oxytoca, Proteus mirabilis,
Salmonella species, other members of the
Enterobacteriaceae, and Pseudomonas aeruginosa (5, 6, 18, 23). Detection of organisms producing these enzymes can be difficult (6, 12, 31, 32), because the presence of ESBLs in a bacterial cell does not always produce a
resistance phenotype when one is using the traditional MIC and disk
diffusion interpretive criteria published by the National Committee for
Clinical Laboratory Standards (NCCLS) (19, 20). Katsanis et
al. (12) demonstrated that the MICs of cefotaxime and
ceftriaxone for E. coli strains that produce ESBLs often do not exceed the numerical threshold for interpretation of a strain as
resistant. Several other studies have shown that even the disk approximation test, first described by Jarlier and colleagues in 1988 (11), fails to detect some ESBL-producing strains (6, 31). In a similar fashion, AmpC -lactamases, which are similar to the chromosomal -lactamases of Enterobacter and
Citrobacter species, can also produce resistance to
extended-spectrum cephalosporins and aztreonam, in addition to the
cephamycins, such as cefoxitin (2, 13). Strains producing
AmpC -lactamases are also emerging in many areas (4, 24),
yet little has been published about the detection of strains producing
these enzymes. AmpC -lactamases are not inhibited by clavulanic acid
or other -lactamase inhibitors. Thus, if an ESBL confirmation test
using clavulanic acid is not performed, many AmpC-producing strains may
be presumed to be ESBL-producing strains.
In 1998, in an effort to improve the detection of ESBL-producing
strains, NCCLS described broth microdilution and disk diffusion screening tests that indicate possible ESBL production in isolates of
K. pneumoniae, K. oxytoca, and E. coli
(21). In 1999, NCCLS went a step further, adding
confirmation tests for ESBL-producing strains and recommending that the
interpretation of test results with extended-spectrum cephalosporins
and aztreonam be changed to "resistant" for ESBL-positive strains
(22).
The study reported herein was undertaken by the Centers for Disease
Control and Prevention (CDC) in cooperation with the Connecticut Department of Public Health and the University of Connecticut in order
to determine if laboratories in Connecticut were able to detect several
common ESBL-producing organisms and an AmpC-producing strain of
E. coli, and to determine if they could differentiate between the two mechanisms of resistance. Furthermore, we attempted to
ascertain whether laboratories were modifying their susceptibility reports for extended-spectrum cephalosporins and aztreonam if an
ESBL-producing organism was detected.
| |
MATERIALS AND METHODS |
Bacterial strains.
Five well-characterized isolates, coded
as CT-6 to CT-10 (two isolates of E. coli and three isolates
of K. pneumoniae), were selected from the strain collection
of the CDC, subcultured, and sent through the Connecticut Department of
Public Health and the University of Connecticut to the 38 laboratories
(31 hospital-affiliated and 7 commercial clinical laboratories) that
routinely send results for reportable diseases to the Connecticut
Department of Public Health.
CT-6 was E. coli 2-76, which had previously been shown to
produce the SHV-8 enzyme (28). CT-7 was an E. coli isolate that produced an AmpC -lactamase. The isolate was
resistant to the extended-spectrum cephalosporins, aztreonam, and the
cephamycins by broth microdilution testing. The strain was shown by
isoelectric focusing to produce a -lactamase with a pI of >8.5,
which is consistent with the presence of an AmpC -lactamase
(2). CT-8, a K. pneumoniae isolate that produces
an SHV-4 enzyme, was obtained from L. B. Reller (Duke University,
Raleigh, N.C.). CT-9, a K. pneumoniae isolate that produced
an SHV-5 enzyme, was provided by M. P. Weinstein (Robert Wood
Johnson Medical School, New Brunswick, N.J.). The identities of the
enzymes produced by CT-8 and CT-9 were confirmed by isoelectric
focusing, which is the reference method for monitoring -lactamase
activity in a bacterial cell. Briefly, the organisms were lysed by a
freeze-thaw procedure (3) and the -lactamases in the
crude extracts were electrophoresed to equilibrium as described by
Matthew et al. (14). CT-10 was K. pneumoniae ATCC
13883 (the K. pneumoniae type strain), which was susceptible
to extended-spectrum cephalosporins and aztreonam. All organism
identifications were confirmed at CDC by traditional biochemical
methods (8). The antimicrobial susceptibility profiles of
the isolates were confirmed by the NCCLS broth microdilution method
(20). Quality control strains included E. coli
ATCC 25922, E. coli ATCC 35218, P. aeruginosa
ATCC 27853, and K. pneumoniae ATCC 700603 (the NCCLS
ESBL-positive control strain).
Confirmation of phenotypes.
Subcultures of all five isolates
were sent back to CDC from the University of Connecticut at the
conclusion of the study. The subcultures returned from the state, and
subcultures of CT-6 through CT-10 from the CDC freezer, were again
tested by broth microdilution using the NCCLS reference method
(20), by Vitek (bioMérieux, Hazelwood, Mo.) using
GNS-102 and NSF-29 cards, and by MicroScan WalkAway (Dade MicroScan,
West Sacramento, Calif.) using Neg-urine MIC-7 panels. All of the
isolates also were retested by isoelectric focusing to ensure that they
still produced the appropriate TEM, SHV, or AmpC -lactamase, all of
which have distinct pI values. The results of the isoelectric focusing
studies were identical for each pair of isolates, and the MICs of
ceftazidime, ceftriaxone, cefotaxime, aztreonam, or cefoxitin obtained
for each organism pair differed by no more than a single twofold dilution.
Instructions to laboratory directors.
The instructions to
the laboratory director indicated that the five organisms (CT-6 to
CT-10) were obtained from blood cultures and should be tested against
the antimicrobial agents that the laboratory would routinely choose for
isolates from patients with suspected cases of sepsis. (This was done
in an attempt to ensure that laboratories would test extended-spectrum
cephalosporins, which might be excluded from testing for isolates from
the urinary tract.) A report form was provided, but it did not contain
a list of antimicrobial agents to test. Rather, the laboratory director had to list the drugs that were tested. The laboratory director was
further instructed to provide the following information: (i) test
method, (ii) quantitative result (MIC or zone diameter), (iii)
interpretation (susceptible, intermediate, or resistant), and (iv) the
interpretation that would be reported on the patient's chart.
| |
RESULTS |
Characteristics of the study strains and test methods.
The
reference broth microdilution MICs of ceftazidime, cefotaxime,
ceftriaxone, and aztreonam for the study strains and the -lactamases
produced by them are shown in Table 1.
Strain CT-10 was included as a cephalosporin-susceptible control. The
susceptibility testing methods used by the 38 laboratories
participating in the survey are shown in Table
2. They included MicroScan WalkAway or
AutoScan (15 laboratories, five different panel types), Vitek (13 laboratories, six different card types), disk diffusion (8 laboratories, including one that used a BioMIC reader [Giles
Scientific, New York, N.Y.]), Sensititre broth microdilution (1 laboratory), and an in-house broth microdilution panel (1 laboratory).
The various combinations of ceftazidime, cefotaxime, ceftriaxone, ceftizoxime, and aztreonam tested by the laboratories are shown in
Table 3. Although ceftizoxime is not
included in the NCCLS list of extended-spectrum cephalosporins
recommended for ESBL detection, we included it because it was the only
extended-spectrum cephalosporin tested by two of the participating
laboratories. The most common combination of drugs tested was
ceftazidime plus ceftriaxone (9 laboratories); 10 laboratories tested
only a single extended-spectrum cephalosporin or aztreonam. Six
laboratories (four MicroScan users and two disk diffusion users) failed
to test any extended-spectrum cephalosporins or aztreonam. None of the
laboratories in Connecticut tested cefpodoxime during this study.
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TABLE 1.
Characteristics of study isolates and susceptibility test
results of participating laboratories listed by
interpretive categorya
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TABLE 2.
Abilities of antimicrobial susceptibility testing methods
to detect decreased susceptibility to extended-spectrum cephalosporins
and aztreonam
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Sensitivities of the various antimicrobial agents for detecting
ESBLs.
The susceptibility test results for the five study
organisms by interpretive category (susceptible, intermediate, and
resistant) reported by the 38 laboratories are shown by organism in
Table 1 and by testing method in Table 2. All of the laboratories that
tested ceftazidime (65.8%) reported a result of either intermediate or
resistant for the four organisms producing an ESBL or AmpC -lactamase. Cefotaxime, ceftriaxone, and aztreonam demonstrated variable sensitivities for detection of the three ESBL-producing strains or the AmpC-producing strain. Ceftizoxime showed the lowest sensitivity of the cephalosporins for detecting ESBL- or AmpC-producing organisms (data not shown). The two laboratories that tested
ceftizoxime as their only extended-spectrum cephalosporin (both Vitek
users) failed to report any of the four resistant organisms as
intermediate or resistant to this drug. The percentage of laboratories
that reported a result of intermediate or resistant with at least one extended-spectrum cephalosporin or aztreonam ranged from 68.4 to
76.3%, depending on the organism (Table 2). Resistance in the SHV-8
strain, which typically tests susceptible to cefotaxime and shows only
intermediate levels of resistance to ceftriaxone and aztreonam by the
broth microdilution reference method, was the most difficult to detect;
54.2% of test results with the extended-spectrum cephalosporins and
aztreonam were reported as susceptible. Surprisingly, the next most
difficult resistance mechanism to detect was that mediated by AmpC,
which typically shows resistance to all extended-spectrum cephalosporins and aztreonam by broth microdilution testing (Table 1).
The SHV-5-producing strain produced the lowest number of susceptible
results. One laboratory (using a MicroScan Neg 8 MIC panel) incorrectly
identified the susceptible control strain (CT-10) as resistant to
ceftazidime but susceptible to the other extended-spectrum cephalosporins (Table 2). Four laboratories using MicroScan breakpoint panels were among the six that failed to test any extended-spectrum cephalosporins or aztreonam. The other two laboratories failing to test
these drugs reported using disk diffusion.
ESBL reporting.
Seven (18.4%) of the 38 laboratories noted on
their report forms that at least one of the five organisms contained a
presumptive ESBL. For these organisms, the results of testing with the
extended-spectrum cephalosporins and aztreonam to be reported on the
"patient's chart" were recorded as resistant based on the
suspected presence of the enzyme. An eighth laboratory noted on its
report forms that all of the isolates except CT-10 were ESBL producers
but still reported CT-6 and CT-8 susceptible to ceftriaxone, contrary to NCCLS guidelines (data not shown). No laboratory differentiated the
AmpC-producing isolate (CT-7) from the other ESBL-producing isolates.
Laboratories modifying reports for at least one organism included three
Vitek users (two reported using the Vitek Expert system), one MicroScan
user, two disk diffusion users, and the one laboratory using an
in-house broth microdilution method. The results for all of the
extended-spectrum cephalosporins and aztreonam tested by each of the
seven laboratories are shown in Table 4, including the changes made to the reports. The Vitek Expert system used
by laboratories A and B failed to recognize the ESBL phenotype in CT-6,
although CT-8 and CT-9 were identified as ESBL producers. Laboratory C
identified CT-8 as an ESBL producer and modified the reporting of
ceftriaxone, cefotaxime, and ceftizoxime results, although the criteria
they used for identification are unclear. Laboratory C did not
recognize CT-9 as an ESBL producer, so the results for the three
extended-spectrum cephalosporins were not modified. The changes
reported by laboratories C through G were initiated by the
microbiologists, while those in laboratories A and B were initiated by
the Vitek Expert system.
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TABLE 4.
Categorical interpretations for key antimicrobial agents,
including changes, following recognition of a presumptive
ESBL producer
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| |
DISCUSSION |
Methods for detecting ESBL-producing bacteria have been evolving
for more than a decade, beginning with the description of the disk
approximation test by Jarlier and colleagues in 1988 (11).
This test, also known as the "double disk" test, uses a clavulanic
acid-containing disk placed in proximity to disks containing
extended-spectrum cephalosporins and aztreonam to demonstrate that the
test strain contains a -lactamase whose activity is inhibited by
clavulanic acid. This simple disk diffusion assay has served as the
reference method for detecting ESBL-producing strains for a number of
years (12, 30, 31). However, some studies have questioned
its sensitivity, and several modifications, including changing the
distance between the disks, have been recommended (5, 31).
Vitek ESBL cards (30), special Etest strips (5, 32), and newer MicroScan panels (16) have also been
evaluated for detecting these types of strains, and all have
demonstrated >90% sensitivity.
The goal of our study, which included all of the laboratories in the
state of Connecticut that routinely perform antimicrobial susceptibility testing, was to determine how well laboratories could
detect ESBL-producing organisms and to determine if the laboratories
could differentiate an AmpC-producing strain from an ESBL-producing
strain. The purpose of the testing was blinded to the participating
laboratories, i.e., detection of ESBL- and AmpC-producing isolates was
not mentioned in the protocol. Ceftazidime, regardless of the testing
method, proved to have adequate sensitivity to detect the
ESBL-producing isolates and the AmpC-producing isolate even when the
traditional NCCLS breakpoints were used (19, 20); none of
the laboratories testing ceftazidime failed to classify the four
resistant strains as either intermediate or resistant. These results
different from those of Moland et al. (16), who reported
that ceftazidime had a sensitivity of only 78% for detection of
ESBL-producing organisms when used in a broth microdilution format
(although they included other enteric organisms besides Klebsiella species and E. coli in their study and
selected a number of strains for which the ceftazidime MICs were 
16
µg/ml). Our testing of three commercial antimicrobial susceptibility
panels and cards confirmed that ceftazidime was sufficiently sensitive to detect strains that produce SHV-4, SHV-5, SHV-8, or AmpC. Thus, laboratories that include ceftazidime in their testing panels are more
likely to detect ESBL-producing strains than those that do not. The
utility of ceftazidime for detecting other -lactamases, such as the
TEM derivatives that are most active on cefotaxime (2, 13),
remains unknown; however, data from CDC (unpublished observations) suggest that ceftazidime should be sufficiently sensitive
to detect most of these strains, particularly if the new screening
breakpoints are used (22). We chose SHV-4 and SHV-5 because
they are common in ESBL-producing organisms that are reported to cause
outbreaks of nosocomial disease (1, 9, 25, 26). The
SHV-8-producing strain (28) was selected because it is
usually more difficult to detect, as was the case in this study. The
difficulty is primarily due to the low concentrations of cefotaxime and
ceftriaxone required to inhibit growth of this E. coli
strain, which, if ceftazidime is not tested, suggest a cephalosporin-susceptible isolate.
Although reports of ESBL-producing strains have been appearing for more
than a decade (11, 17, 29), laboratories have been slow to
embrace newer ESBL detection methods, in part because the clinical
importance of identifying such strains remained unclear (7).
However, there is now increasing clinical evidence that underscores the
importance of detecting these strains (27, 33). While the
Vitek Expert system can detect some ESBLs, two different cards failed
to identify the SHV-8-producing strain of E. coli (Table 4).
These algorithms often incorporate the results of antimicrobial agents,
such as cefoxitin and amoxicillin-clavulanic acid, which may not fit
into classical ESBL definitions for all strains; therefore, it is
important that microbiologists continue to review their susceptibility
test results manually in order to identify presumptive ESBL producers,
as was done by the other four laboratories that modified their results
(Table 4).
In the most recent NCCLS document, M100-S9, both screening breakpoints
to enhance the detection of potential ESBL-producing strains and
confirmation tests using clavulanic acid in conjunction with
ceftazidime and cefotaxime are described (22); however, there is no mention of testing or reporting results for AmpC-producing isolates. Although we assumed that AmpC-producing isolates would show
resistance to all oxyiminocephalosporins and therefore would be easy to
detect, our data suggest that this is not the case with many of the
susceptibility testing methods being used in laboratories in the United
States. NCCLS recommends modifying the extended-spectrum cephalosporin
and aztreonam results only for ESBL-producing strains; however, the
laboratory will not know whether the organism produces an ESBL or an
AmpC -lactamase if the confirmation tests with clavulanic acid are
not performed. Thus, as was shown here, some AmpC-producing strains are
likely to be classified as ESBL producers, and the interpretation of their susceptibility results for the extended-spectrum cephalosporins and aztreonam is likely to be changed to reflect resistance. Given the
likelihood that AmpC-producing strains would not respond to extended-spectrum cephalosporins or aztreonam (4, 24), we believe that modifying the interpretations to reflect resistance to
extended-spectrum cephalosporins and aztreonam for AmpC-producing strains is reasonable. While reporting a mechanism of resistance, such
as "presence of an ESBL-producing strain," on a laboratory report
is unlikely to aid clinicians in the selection of effective antimicrobial agents, modification of cephalosporin results on laboratory reports should increase the accuracy of the susceptibility test reporting.
In this study, which was conducted before the release of M100-S9, it
was surprising that 6 of the 38 laboratories failed to test any
extended-spectrum cephalosporins or aztreonam against isolates of
gram-negative bacilli that were identified as blood culture isolates.
Table 1 of both NCCLS documents M2 and M7 (19, 20)
recommends testing extended-spectrum cephalosporins routinely, although
the laboratory has the opinion of not reporting the results of these
drugs for organisms that are susceptible to first-generation cephalosporins. In this case, the six laboratories did not test the
drugs. Given the rising incidence of ESBL-producing strains in the
United States (6, 17, 27, 33), we believe that this provides
false economy for the laboratory, as does testing of drugs, such as
ceftizoxime, that are ineffective detectors of ESBL production.
In summary, the results of this study suggest that detection of
ESBL-producing strains remains a problem in the United States and that
strains of Klebsiella and E. coli that produce
ESBLs and AmpC -lactamases are likely to be overlooked in some
hospitals. These data also show that ceftazidime is a sensitive
indicator of ESBL- and AmpC-producing strains. While cefpodoxime may
work well, none of the laboratories tested this agent during this
study, perhaps because at the time of testing it was not available on most Vitek or MicroScan panels. We believe strongly that
extended-spectrum cephalosporins, perhaps in parallel with aztreonam,
should be tested routinely in the laboratory against gram-negative
agents of sepsis, particularly if resistance to first-generation
cephalosporins is evident. Although Emery and Weymouth (7)
suggested that ESBL screening using additional tests is not
cost-effective, our results show that with careful selection of panels,
cards, and disks, routine testing strategies may detect many ESBLs
without additional expense.
| |
ACKNOWLEDGMENTS |
We thank Jana M. Swenson, Kamile Rasheed, Bertha Hill, James W. Biddle, and Caroline M. O'Hara for excellent technical assistance and
helpful review of the manuscript.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Nosocomial
Pathogens Laboratory Branch (G08), Hospital Infections Program, Centers for Disease Control and Prevention, 1600 Clifton Rd., Atlanta, GA
30333. Phone: (404) 639-3246. Fax: (404) 639-1381. E-mail: fnt1{at}CDC.GOV.
| |
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Journal of Clinical Microbiology, December 1999, p. 4065-4070, Vol. 37, No. 12
0095-1137/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
