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Journal of Clinical Microbiology, September 1998, p. 2575-2579, Vol. 36, No. 9
0095-1137/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Can Results Obtained with Commercially Available MicroScan
Microdilution Panels Serve as an Indicator of 
-Lactamase
Production among Escherichia coli and
Klebsiella Isolates with Hidden Resistance to
ExpandedSpectrum Cephalosporins and Aztreonam?
Ellen Smith
Moland,*
Christine C.
Sanders, and
Kenneth S.
Thomson
Center for Research in Anti-Infectives and
Biotechnology, Department of Medical Microbiology and Immunology,
Creighton University, Omaha, Nebraska 68178
Received 30 March 1998/Returned for modification 15 May
1998/Accepted 14 June 1998
 |
ABSTRACT |
Among clinical isolates of Escherichia coli,
Klebsiella pneumoniae, and Klebsiella oxytoca,
there is an ever-increasing prevalence of 
-lactamases
that may confer resistance to newer -lactam antibiotics that is
not detectable by conventional procedures.
Therefore, 75 isolates of these species producing well-characterized
-lactamases were studied using two MicroScan
conventional microdilution panels, Gram Negative Urine MIC 7 (NU7)
and Gram Negative MIC Plus 2 (N+2), to determine if results could
be utilized to provide an accurate indication of -lactamase
production in the absence of frank resistance to expanded-spectrum
cephalosporins and aztreonam. The enzymes studied included
Bush groups 1 (AmpC), 2b (TEM-1, TEM-2, and SHV-1), 2be (extended
spectrum -lactamases [ESBLs] and K1), and 2br, alone and in
various combinations. In tests with E. coli and K. pneumoniae and the NU7 panel, cefpodoxime MICs of 
2 µg/ml
were obtained only for isolates producing ESBLs or AmpC
-lactamases. Cefoxitin MICs of >16 µg/ml were obtained for all
strains producing AmpC -lactamase and only 1 of 33 strains producing ESBLs. For the N+2 panel, ceftazidime MICs of 4
µg/ml correctly identified 90% of ESBL producers and
100% of AmpC producers among isolates of E. coli and
K. pneumoniae. Cefotetan MICs of 8 µg/ml were obtained for seven of eight producers of AmpC
-lactamase and no ESBL producers. For tests performed with
either panel and isolates of K. oxytoca, MICs of
ceftazidime, cefotaxime, and ceftizoxime were elevated for strains
producing ESBLs, while ceftriaxone and aztreonam MICs separated
low-level K1 from high-level K1 producers within this species. These
results suggest that microdilution panels can be used by
clinical laboratories as an indicator of certain -lactamases that
may produce hidden but clinically significant resistance
among isolates of E. coli, K. pneumoniae, and
K. oxytoca. Although it may not always be possible to
differentiate between strains that produce ESBLs and those that
produce AmpC, this differentiation is not critical since
therapeutic options for patients infected with such organisms are
similarly limited.
| |
INTRODUCTION |
Resistance to -lactam antibiotics
among clinical isolates of gram-negative bacilli is most often due to
the production of -lactamases (26, 28). Until
recently, -lactamase-mediated resistance was readily detected
by a variety of methods used routinely by the clinical laboratory to
ascertain antimicrobial susceptibility. However, numerous changes in
-lactamases of gram-negative bacteria have been occurring over the
last decade (4, 11, 13, 32). Some of these have produced new
forms of older enzymes such as the extended-spectrum -lactamases
(ESBLs), derivatives of the older TEM and SHV enzymes that now can
hydrolyze newer cephalosporins and aztreonam (4, 32).
Other changes have involved the moving of the ampC gene,
characteristically a chromosomal gene responsible for inducible
-lactamase production in genera like Enterobacter, Serratia, and Pseudomonas, onto plasmids that are
now being found in strains of Escherichia coli and
Klebsiella pneumoniae (4, 32).
Unfortunately, resistance to the expanded-spectrum cephalosporins
and aztreonam of many strains producing ESBLs and plasmid derivatives of AmpC -lactamases is not readily apparent in routine susceptibility tests that utilize the current National Committee for
Clinical Laboratory Standards (NCCLS) breakpoints
(10). This is especially true for isolates of E. coli and Klebsiella (32). Thus, the
inability to detect clinically relevant resistance in these
organisms has been responsible for the appearance and spread of
such strains in numerous hospitals without any suspicion by the
laboratory or physicians of their presence (14, 32).
The increasing incidence of ESBLs and other new -lactamases
(11) in strains of the family Enterobacteriaceae
isolated from patients has stimulated the need for new methods to
detect the -lactamases that are responsible for clinically relevant
resistance that is not apparent in routine susceptibility tests
(2, 3, 5, 6, 8, 14, 17, 21, 23, 24, 30, 34). There are a
number of approaches currently under consideration for the detection of
ESBLs (7, 10, 18, 27, 31, 33, 35). However, until these
become available, there must be some way in which the clinical
laboratory can become suspicious of strains potentially possessing
these enzymes. Several approaches to screen for the presence of
ESBLs have been suggested (9, 15, 16, 32, 33). One
possibility includes the use of modified breakpoints for standard
methods of susceptibility testing as suggested by the NCCLS
(15, 16). With these modifications, the NCCLS has suggested that strains of E. coli and
Klebsiella spp. be screened for production of ESBLs by
utilizing new interpretive criteria for MIC or disk diffusion testing
with ceftazidime, cefotaxime, ceftriaxone, cefpodoxime, and aztreonam
(15, 16). Somewhat similar criteria were suggested earlier
by Thomson et al. (32).
To date, there has been no systematic study to assess the ability of
several proposed approaches to detect the presence of ESBLs or
other -lactamases capable of producing hidden resistance to
expanded-spectrum cephalosporins and aztreonam in E. coli and Klebsiella. Therefore, a study was designed
using a commercial broth microdilution test procedure available for use
in the routine clinical laboratory to determine the best method for
indicating the presence of such enzymes. Strains of E. coli and Klebsiella spp. for this study were chosen
either because they produced -lactamases known to cause hidden
resistance to expanded-spectrum cephalosporins and aztreonam or because
they produced other types of -lactamases that might give
false-positive results in nonspecific tests for the former enzymes.
| |
MATERIALS AND METHODS |
Strains.
Tests were performed with 75 isolates of
E. coli (n = 31), K. pneumoniae (n = 31), and Klebsiella
oxytoca (n = 13). Forty-four of these isolates
were chosen because they possessed a -lactamase (ESBL and/or
AmpC -lactamase) that should confer clinically relevant resistance
to expanded-spectrum cephalosporins and aztreonam but the MICs obtained
in routine broth microdilution tests were 
16 µg/ml with ceftazidime
or aztreonam or 32 µg/ml with ceftriaxone, ceftizoxime, or
cefotaxime. Thus, these strains were defined as having hidden
resistance to expanded-spectrum cephalosporins and aztreonam. The other
31 strains were chosen because they were known to produce other
-lactamases some of which, such as the K. oxytoca K1
enzyme, were biochemically very similar to ESBLs (4).
These strains were collected from multiple centers across the United
States and Europe. The strains were stored at 
70°C in a mixture of
horse serum and brain heart infusion broth. These isolates were
subcultured only once, and the presence of the known -lactamase was
confirmed. All of the 75 isolates were obtained from clinical sources
except for 13 laboratory strains of E. coli. For the
purposes of this study, the organisms were divided into groups
according to the type of -lactamase produced. These groups included
(i) ESBLs, (ii) AmpC, (iii) high-level K1 producers, and (iv) other
-lactamases (Table 1). Within the AmpC
group, there were strains of E. coli that hyperproduced
their chromosomal enzyme as well as those that had acquired a
plasmid-derived AmpC -lactamase from another species. A number of
organisms produced multiple -lactamases, and levels of -lactamase
expression varied as well. One strain produced two different ESBLs
and a plasmid derivative AmpC -lactamase. Since preliminary studies
with this strain indicated that results of susceptibility tests
reflected the activity of the broader-spectrum AmpC -lactamase, this
strain was considered in the AmpC group. Other organisms with
combinations of -lactamases were assigned to the group representing
the broader-spectrum enzymes (e.g., organisms possessing ESBL and
TEM-1 were assigned to the ESBL group), or if no dominant enzymes
were present, the strain would be assigned to the other -lactamases
group (e.g., low-level K1, TEM-1, SHV-1, etc.). All -lactamase
identifications were confirmed in the laboratory by appropriate
biochemical or molecular procedures including isoelectric focusing
substrate profile, inhibitor profile, plasmid isolation, recombinant
DNA techniques, and transformations (1, 12, 19, 25, 29, 35).
The quality control strain utilized in this study was E. coli ATCC 25922 (15).
Susceptibility tests.
Antibiotic susceptibilities were
determined according to the manufacturer's recommendations by
overnight microdilution method with commercial dehydrated panels
provided by Dade Behring MicroScan (Sacramento, Calif.) that were read
by the Walkaway 40 and interpreted according to NCCLS criteria
(15). The two panels studied were the Gram Negative Urine
MIC 7 (NU7) and the Gram Negative MIC Plus 2 (N+2). They were selected
on the basis of the concentrations and types of -lactam drugs in the
panel from among a number of panels available to the routine clinical
laboratory (Table 2). Since previous
studies had indicated that cefpodoxime was the single best indicator of
the presence of ESBLs (33) and that ceftazidime,
cefotaxime, ceftriaxone, or aztreonam may also be used to indicate the
presence of ESBLs (15, 16), the two commercially available panels containing as many of these drugs as possible with
concentrations as low as 2 µg/ml were chosen for study. These also contained at least one cephamycin which had the potential to help
discriminate ESBLs from AmpC -lactamases. The antibiotics listed
in Table 2 are those that were potentially useful for the detection and
differentiation of the -lactamases present in these strains.
Although there were additional -lactams and other classes of
antibiotics on these panels that are not listed in Table 2, these were
not useful for the current study and will not be considered further.
| |
RESULTS |
E. coli and K. pneumoniae.
For tests
performed with the N+2 panel, no single drug at any one concentration
accurately differentiated between strains producing ESBLs, AmpC, or
other -lactamases (Table 3). Although the breakpoint of 2 µg/ml of aztreonam or ceftazidime that is currently recommended by NCCLS did correctly identify most ESBL producers (82 to 91%), it also included most strains producing AmpC
-lactamase. For ceftazidime, MICs of 2µg/ml were obtained for two of three strains of K. pneumoniae producing high
levels of SHV-1 -lactamase, giving a false-positive rate of 10% for producers of -lactamases other than ESBLs and AmpC (Table 3). These false positives could be eliminated by raising the ceftazidime breakpoint to 4 µg/ml, just slightly reducing the number of
ESBL producers identified at this breakpoint from 30 to 29. The
four ESBL producers for which ceftazidime MICs were <4 µg/ml
included three E. coli isolates and one K. pneumoniae isolate with SHV-derived ESBLs. The MIC of
ceftriaxone was 4 µg/ml for one of these three strains, while
the MIC of cefotaxime was 4 µg/ml for another. MICs of
aztreonam and ceftizoxime were not elevated for the two remaining
strains. Thus, 94% of ESBL producers and 100% of AmpC producers
were indicated by ceftazidime, ceftriaxone, or cefotaxime MICs of 4
µg/ml. The lower percentage of strains with ESBLs or AmpC
-lactamases identified by cefotaxime, ceftriaxone, or ceftizoxime MICs was most likely related to the absence of concentrations below 2 µg/ml on the panel. Cefotetan did not completely discriminate between producers of AmpC and ESBLs, although MICs of 8 µg/ml were obtained in tests with all but one AmpC producer
(Table 3).
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TABLE 3.
Detection of -lactamases among E. coli
and K. pneumoniae isolates by various interpretive
criteria applied to results obtained in tests with the N + 2 panel
|
|
In tests with the NU7 panel, cefpodoxime clearly was the best single
antibiotic in its ability to discriminate the producers
of ESBLs or
AmpC
-lactamases from other types of
-lactamases
(Table
4). Cefpodoxime MICs of
2 µg/ml
were obtained in tests
with all of the ESBL or AmpC producers,
while MICs in tests with
producers of other
-lactamases were
1
µg/ml. In fact, MICs of
cefpodoxime were
4 µg/ml in tests
with all of the ESBL or AmpC
producers. Cefoxitin differentiated
somewhat between producers
of AmpC and ESBLs (Table
4). MICs of
cefoxitin were >16 µg/ml
for all strains producing AmpC
-lactamase and for only one strain
producing an ESBL, which was
a
K. pneumoniae isolate (Table
4).
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TABLE 4.
Detection of -lactamases among E. coli
and K. pneumoniae isolates by various interpretive
criteria applied to results obtained in tests with the
NU7 panel
|
|
K. oxytoca.
In tests with the N+2 panel,
ceftazidime MICs were 2 µg/ml, cefotaxime MICs were 4
µg/ml, and ceftizoxime MICs were 4 µg/ml only for
ESBL producers (Table 5). In fact,
MICs of ceftazidime and ceftizoxime were 16 µg/ml for ESBL
producers. Ceftriaxone MICs of 4 µg/ml or aztreonam MICs of 2
µg/ml in the absence of elevated MICs for ceftazidime,
cefotaxime, or ceftizoxime indicated high-level producers of the K1
-lactamase. MICs of none of these drugs were elevated in tests with
low-level producers of K1 with or without other -lactamases. In
tests with the NU7 panel, ceftazidime MICs of >16 µg/ml were
obtained only in tests with ESBL producers, while ceftriaxone MICs
but not ceftazidime MICs were elevated for high-level producers of K1
-lactamase (Table 5).
| |
DISCUSSION |
The results of this study indicate that broth microdilution panels
currently available to the clinical laboratory can provide a vehicle
for the detection of -lactamases capable of producing hidden
resistance to expanded-spectrum cephalosporins and aztreonam in
isolates of E. coli, K. pneumoniae, and
K. oxytoca. Expanding the current study with additional
strains that produce ESBLs and other sorts of -lactamases might
be useful for fine-tuning the conclusions presented here. A panel
containing cefpodoxime was the most useful in identifying strains
possessing ESBLs or AmpC -lactamases, although this drug could
not be used to distinguish between these two types of -lactamases.
However, this should not be considered a liability since the
therapeutic options for patients infected with strains of these
species possessing ESBLs or AmpC -lactamases are limited and
usually involve a carbapenem as the drug of choice (32). For
panels not containing cefpodoxime, maximal identification of strains
possessing ESBLs or AmpC -lactamases was obtained in tests with
ceftazidime.
The use of a cephamycin to discriminate between producers of AmpC and
ESBLs was not completely reliable as one strain with AmpC
-lactamase was susceptible to cefotetan (MIC, <8 µg/ml) and
one strain without AmpC appeared to be resistant to cefoxitin (MIC,
>16 µg/ml). The cefoxitin resistance was most probably due to
the fact that a porin mutation in strains of K. pneumoniae expressing an ESBL often leads to resistance to the
cephamycins (20, 22). Although precise separation of AmpC
from ESBL producers was not possible in single-drug tests like
those available on conventional microdilution panels, it can be
concluded from the results of this study that cephamycin-susceptible
strains of E. coli, K. pneumoniae, and
K. oxytoca are highly likely to be producers of
ESBLs and not AmpC -lactamases.
The results of this study also suggest that the recommendations of the
NCCLS (15) need some modification. First, the
recommendations should be modified to indicate that they
apply to both ESBLs and AmpC -lactamases that may produce hidden
resistance to expanded-spectrum cephalosporins and aztreonam. Second,
if ceftazidime is to be used as a screen for ESBLs and AmpC
-lactamases, a concentration of 4 µg/ml is preferred to a
concentration of 2 µg/ml. Third, recommendations for screening
for K. oxytoca must be different from those for
E. coli and K. pneumoniae. For
K. oxytoca, cefodoxime, ceftriaxone, and aztreonam
are not adequate drugs for screening for ESBLs since MICs for
high-level producers of the K1 -lactamase may be 2 µg/ml
with these antibiotics. Only cefotaxime, ceftazidime, and ceftizoxime
were reliable indicators of the presence of ESBLs in K. oxytoca.
The results of this study clearly show that more-specific tests are
needed for the identification of AmpC -lactamases and ESBLs in
isolates of E. coli, K. pneumoniae, and
K. oxytoca. Such tests are currently under study
(7, 10, 18, 27, 31, 33, 35) and by necessity involve the use
of combinations of -lactam antibiotics with inhibitors of
-lactamases. However, until these tests become available for routine
use in the clinical laboratory, it should be possible for the
laboratory to gain a high degree of suspicion concerning the
presence of ESBLs or AmpC -lactamases from the results of
conventional antimicrobial susceptibility tests. As summarized in Table
6, for laboratories using the N+2 or NU7
panel, an isolate of E. coli or K. pneumoniae should be suspected of harboring an ESBL or an AmpC
-lactamase if cefpodoxime MICs are 2 µg/ml or if MICs of
ceftazidime, ceftriaxone, or cefotaxime are 4 µg/ml. If the strain
is susceptible to the cephamycins, it is most likely to have an
ESBL rather than an AmpC -lactamase. It is interesting to note
that with both of the panels tested, false positives indicating the
presence of AmpC -lactamase or ESBLs were not encountered with
the interpretive criteria. Thus, no strains producing other
-lactamases appeared falsely positive for ESBLs
(AmpC/ESBL) or AmpC -lactamase. The only false positives encountered with the interpretive criteria indicating the presence of
AmpC -lactamase specifically or the presence of ESBLs
specifically involved strains producing ESBLs or AmpC
-lactamase, respectively. For K. oxytoca, elevated
MICs of ceftazidime indicate the presence of an ESBL while
elevated MICs of ceftriaxone indicate a high-level producer of K1
-lactamase. If these guidelines are followed, they should greatly
enhance the ability of a laboratory to suspect the presence of
ESBLs or AmpC -lactamases among E. coli,
K. pneumoniae, and K. oxytoca isolates.
| |
ACKNOWLEDGMENTS |
This study was supported by Dade MicroScan (Sacramento, Calif.).
Thanks to Stacey Edward, Stacey Morrow, and Michelle Johnson for
excellent technical support on this project and to Karen Wise for
assisting in the preparation of the manuscript. Thanks also to J. Godsey for making this study possible.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Center for
Research in Anti-Infectives and Biotechnology, Department of Medical
Microbiology and Immunology, Creighton University, Omaha, NE
68178. Phone: (402) 280-1881. Fax: (402) 280-1225. E-mail:
esmoland{at}creighton.edu.
| |
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0095-1137/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
