Previous Article | Next Article 
Antimicrobial Agents and Chemotherapy, December 2001, p. 3548-3554, Vol. 45, No. 12
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.12.3548-3554.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Cefepime, Piperacillin-Tazobactam, and the
Inoculum Effect in Tests with Extended-Spectrum
-Lactamase-Producing Enterobacteriaceae
Kenneth S.
Thomson* and
Ellen Smith
Moland
Center for Research in Antiinfectives and
Biotechnology, Department of Medical Microbiology and
Immunology, Creighton University School of Medicine, Omaha,
Nebraska 68178
Received 17 January 2001/Returned for modification 31 May
2001/Accepted 28 August 2001
 |
ABSTRACT |
There is little information about the clinical effectiveness of
cefepime and piperacillin-tazobactam in the treatment of infections caused by extended-spectrum 
-lactamase (ESBL)-producing pathogens. Some inferences have been drawn from laboratory studies, which have
usually involved only one or a few strains of ESBL-producing Klebsiella pneumoniae or Escherichia coli
that produced only a limited range of ESBLs. Such studies are indirect,
sometimes conflicting, indicators of efficacy. To extend previous
laboratory findings, a study was designed to investigate organism-drug
interactions by determining the in vitro activities of eight parenteral
-lactam agents against 82 clinical and laboratory strains of
Klebsiella, Escherichia,
Enterobacter, Citrobacter,
Serratia, Morganella, and
Proteus species that produced 22 different ESBLs, alone
or in combination with other -lactamases. Activities were determined in broth microdilution MIC tests using standard and 100-fold-higher inocula. An inoculum effect, defined as an eightfold or greater MIC
increase on testing with the higher inoculum, was most consistently detected with cefepime, cefotaxime, and ceftriaxone and least frequently detected with meropenem and cefoteten.
Piperacillin-tazobactam was intermediate between these two groups of
agents. Although the inoculum effect is an in vitro laboratory
phenomenon, if it has any predictive value in identifying increased
risk of therapeutic failure in serious infections, these results
support suggestions that cefepime may be a less-than-reliable agent for
therapy of infections caused by ESBL-producing strains.
| |
INTRODUCTION |
Extended-spectrum -lactamases (ESBLs) are novel
-lactamases produced by a variety of
gram-negative bacilli. The distinguishing feature of these enzymes is
that compared to the broad-spectrum -lactamases, such as TEM-1,
TEM-2, SHV-1, and others, ESBLs have extended substrate profiles which
permit hydrolysis of aztreonam and expanded-spectrum cephalosporins
such as cefotaxime, ceftriaxone, ceftazidime, cefepime, and others. To
date, ESBLs are most commonly produced by isolates of Klebsiella
pneumoniae and, to a lesser extent, Escherichia coli
(8, 9, 12, 27, 30, 40, 44), but infections, colonization,
and nosocomial spread involving other ESBL-producing organisms (such as
Morganella morganii; Serratia marcescens;
Shigella dysenteriae; several species of
Enterobacter, Salmonella, Proteus, and
Citrobacter; Pseudomonas aeruginosa; Burkholderia cepacia; and Capnocytophaga
ochracea) have been reported (45). A major problem
with ESBLs is their capacity to cause therapeutic failures with
cephalosporins and aztreonam when the host organism appears to be
susceptible to these agents in laboratory tests (5, 13, 15, 27,
30, 44, 47). In response to this problem, the National Committee
for Clinical Laboratory Standards (NCCLS) recommends that laboratories
should report ESBL-producing isolates of E. coli or
Klebsiella spp. as resistant to all penicillins, cephalosporins (including cefepime and cefpirome), and aztreonam irrespective of in the vitro test results (23). This
recommendation does not extend to ESBL-producing organisms of other genera.
Cefepime and cefpirome are often substantially more active in vitro
than earlier cephalosporins against ESBL-producing pathogens (38,
46). This probably stems from their greater intrinsic potency
due to more rapid permeation through the outer membrane (37). Clinical data determining the efficacy of these
agents in ESBL-associated infections are lacking. In vitro studies with high inocula show that the MICs of cefepime (14, 19, 43) and cefpirome (19) for ESBL-producing isolates of K. pneumoniae and E. coli are often greatly elevated,
suggesting that these agents are inactivated by ESBLs. Animal models of
infection with these organisms have produced both successful and
unsuccessful therapeutic outcomes with cefepime (34, 43).
The in vitro and animal studies have been somewhat limited in scope,
comprising investigations with only two bacterial species and with only
a few types of ESBLs. It is unknown if the findings of these studies can be extended to other types of ESBLs and to other ESBL-producing pathogens. Indeed, it has been suggested that there is great
variability among ESBLs in their interactions with cefepime, with
SHV-derived ESBLs exhibiting more of a tendency to decrease cefepime
activity than TEM-derived ESBLs (38).
There are also questions about whether -lactamase inhibitor
combinations should be used for therapy of infections caused by
ESBL-producing pathogens. Current data are incomplete and sometimes conflicting. Many ESBL-producing isolates of K. pneumoniae
or E. coli are susceptible in vitro to
piperacillin-tazobactam (3, 7, 11, 24), but MICs may
increase substantially in tests with a higher-than-standard inoculum
(10, 14). Efficacy has been reported in animal models of
infection (17, 21, 32, 33, 43), but clinical failure was
reported in a patient with spontaneous bacterial peritonitis who was
awaiting liver transplantation for end-stage liver disease
(28). In some of these reports the presence of ESBLs was
inferred from indirect tests and the actual enzymes involved were not
identified (14, 28). This precludes analysis of which
particular ESBLs were associated with favorable or unfavorable
outcomes. In addition, minimal and only presumptive characterization of
resistance mechanisms may not take into account the possibility that
other resistance mechanisms may have contributed to the findings.
The present study was designed to investigate further the activity of
cefepime and piperacillin-tazobactam against ESBL-producing strains by
determining the activities of these two agents and six other parenteral
-lactam agents in standard- and high-inoculum MIC tests against nine
species of Enterobacteriaceae that produced 22 different
TEM-, SHV-, or Toho-type ESBLs. To represent the more recent clinical
isolates, which seem to be continually evolving, often acquiring
additional -lactamases, the study included ESBL-producing isolates
that produced multiple (up to five) other -lactamases.
| |
MATERIALS AND METHODS |
Strains.
Tests were performed with a panel of 82 ESBL-producing clinical and laboratory strains including E. coli (n = 35), K. pneumoniae (n = 19), Klebsiella oxytoca
(n = 3), Proteus mirabilis
(n = 1), Citrobacter koseri
(n = 1), Citrobacter freundii
(n = 2), Enterobacter cloacae
(n = 4), Enterobacter aerogenes
(n = 10), M. morganii (n = 1), and S. marcescens (n = 6). The
strains were chosen to provide a wide variety of ESBLs (produced either
alone or in combination with one or more other -lactamases) and were
collected from multiple centers across North America, Europe, Africa,
and Asia. The panel included 13 genetically constructed, isogenic
E. coli C600N strains that produced the enzymes TEM-3,
TEM-4, TEM-5, TEM-7, TEM-8, TEM-10, TEM-12, TEM-28, TEM-43, SHV-2,
SHV-3, SHV-4, and SHV-7 (4). Other ESBLs included in the
study were TEM-6, TEM-9, TEM-16, TEM-24, TEM-26, TEM-43, TEM-50, SHV-5,
Toho-1, and Toho-2 and several as yet unidentified ESBLs. Other
(non-ESBL) -lactamases included in the study for comparison with the
ESBLs were TEM-1, SHV-1, SHV-10, AmpC, and K1. All -lactamase
identifications were confirmed in our laboratory by the appropriate
biochemical or molecular procedures, such as isoelectric focusing
(20, 39), substrate profile (1, 25),
inhibitor profile (39), plasmid isolation, recombinant DNA
techniques, and transformations (36).
Quality control strains used were E. coli ATCC 25922, E. coli ATCC 35218 (TEM-1), E. coli MISC 128 (SHV-1), K. pneumoniae 156 (SHV-1), and E. coli
PAB-C15 (SHV-3).
Susceptibility tests.
Antibiotic susceptibilities were
determined by microdilution MIC methodology using inocula that differed
100-fold in density. The inocula comprised approximately
105 (standard inoculum) and
107 CFU/ml suspended in Mueller-Hinton broth
(catalog no. CM405; Oxoid, Basingstoke, United Kingdom). The
standard-inoculum tests were by NCCLS methodology (22). An
inoculum effect was defined as an eightfold or greater increase in MIC
on testing with the higher inoculum. The microdilution panels, prepared
in-house and stored frozen at 
70°C, contained doubling dilutions of
meropenem, cefoteten, cefotaxime, ceftazidime, ceftriaxone, cefepime,
aztreonam, and piperacillin in combination with tazobactam (4 µg/ml).
The antibiotic powders were kindly provided by their manufacturers.
| |
RESULTS |
Tests with isogenic E. coli C600N strains.
Testing with the E. coli C600N host strain provided a
genetically more uniform background by eliminating the confounding
influences that may arise with more heterogeneous clinical strains. In
these tests, cefotaxime, ceftriaxone, and cefepime were the agents most frequently associated with inoculum effects. All ESBLs except SHV-4
were associated with an inoculum effect with these three agents (Table
1 shows representative results).
Ceftazidime was affected by fewer ESBLs but was associated with
inoculum effects with organisms producing TEM-3, TEM-5, TEM-7, TEM-8,
TEM-10, TEM-12, TEM-28, TEM-43, or SHV-3 ESBLs. Aztreonam was
associated with inoculum effects in tests with strains producing TEM-5,
TEM-7, TEM-8, TEM-12, TEM-28, TEM-43, and SHV-2.
Piperacillin-tazobactam was only associated with inoculum effects in
tests with strains producing SHV-derived ESBLs, and not in tests with
strains producing TEM-derived ESBLs. There were no inoculum effects in
tests with meropenem and cefoteten.
Tests with species lacking an inducible chromosomal AmpC
-lactamase. (i) K. pneumoniae, K.
oxytoca, E. coli, C. koseri, and
P. mirabilis
Being obtained from diverse clinical
sources, the isolates of these five species were more heterogeneous and
produced a greater range of -lactamases than the E.
coli C600 panel. Many of the K. pneumoniae
isolates produced multiple -lactamases, sometimes including two
ESBLs. Although the K. pneumoniae strains tended to be
somewhat more resistant overall than the
E. coli strains (Tables 2 and
3), probably reflecting the greater
incidence of multiple -lactamase production, the results for all the
species within this group appeared to be generally similar.
Cefepime was associated with inoculum effects in 100% of evaluable
tests with
K. pneumoniae and
E. coli (i.e.,
excluding those
which could not be evaluated because of off-scale
MICs), making
it slightly more affected than ceftriaxone and cefotaxime
(both
had inoculum effects in 97% of tests) (Tables
2 and
3). The
propensity for inoculum effects with these drugs was reflected
in
comparisons of the percentages of isolates of
E. coli and
K. pneumoniae susceptible to a concentration of each agent
of 8 µg/ml
in the lower- and higher-inoculum tests (Tables
2 and
3).
For
example, 79% of the
E. coli isolates were susceptible
to a concentration
of cefepime and ceftriaxone of 8 µg/ml in the
standard-inoculum
tests, but only 5% of isolates were susceptible to
each agent
in the higher-inoculum
tests.
In the tests which could be evaluated, the Toho-1 and Toho-2 enzymes
were associated with inoculum effects with cefotaxime,
ceftriaxone,
cefepime, and aztreonam, but not with ceftazidime.
Only Toho-2 was
associated with an inoculum effect with piperacillin-tazobactam
(data
not shown). SHV-10 was associated with an inoculum effect
only with
ceftazidime (Table
4). Three isolates of
K. pneumoniae (strains 98, 221, and 222) were highly
susceptible to at least
one of cefotaxime, ceftriaxone, ceftazidime, or
aztreonam with
standard-inoculum MICs of these drugs below the NCCLS
ESBL screening
concentration of 2 µg/ml (Table
4).
Piperacillin-tazobactam inhibited 95% of
E. coli isolates
at the susceptible breakpoint of 16 and 4 µg/ml (for piperacillin
and
tazobactam, respectively) in the standard-inoculum tests and
inhibited
58% of isolates at this concentration in the higher-inoculum
tests
(Table
2). It was less active in tests with
K. pneumoniae,
inhibiting 67 and 22% of isolates, respectively, at this
concentration.
In contrast to the results with the isogenic
E. coli panel, piperacillin-tazobactam
was subject to inoculum
effects in the presence of certain TEM-derived
ESBLs. In tests with
E. coli, inoculum effects were associated
with production of
TEM-9, TEM-26, TEM-50, and also with the combination
of TEM-12 and
TEM-1 (data not shown). Of these enzymes, only TEM-12
was present in
the isogenic
E. coli C600N panel and then was produced
alone. This suggests that the coproduction of TEM-1 may have
contributed
to the inoculum effect in the isolate that produced both
enzymes.
In tests with
K. pneumoniae, inoculum effects were
associated
with TEM-8 and TEM-16 (data not shown). TEM-8 was present in
the
isogenic
E. coli C600N panel. TEM-16 was
not.
Meropenem at 0.12 and at 4 µg/ml inhibited all isolates in the
standard-inoculum tests and the higher-inoculum tests, respectively,
and cefoteten at 2 and at 32 µg/ml inhibited all isolates in the
standard-inoculum tests and the higher-inoculum tests, respectively
(Tables
2 and
3). Some
K. pneumoniae isolates, such as
strain
98 in Table
4, show an inoculum effect in tests with meropenem
(six strains) and/or cefoteten (seven
strains).
(ii) C. freundii, E. aerogenes,
E. cloacae, M. morganii, and S.
marcescens
In addition to their chromosomally encoded
AmpC -lactamases, the 23 isolates of C. freundii,
E. aerogenes, E. cloacae, M. morganii, and S. marcescens produced at least
one of the ESBLs TEM-3, SHV-2, SHV-3, SHV-4, and SHV-5 or an
unidentified TEM-derived ESBL. Five isolates produced three
-lactamases.
In standard-inoculum tests, all isolates were susceptible to meropenem,
with cefepime being the next most active agent (96%
susceptible)
(Table
5). Fourteen isolates (61%) were
susceptible
to at least one of the cephalosporins, cefotaxime,
ceftriaxone,
or ceftazidime. Some cephalosporin MICs were very low:
e.g., 0.06
µg/ml for cefepime, 1 µg/ml for ceftazidime and
ceftriaxone, and
2 µg/ml for cefotaxime (Table
4). In the
higher-inoculum tests,
inoculum effects occurred with all agents,
reflecting the presence
of the AmpC-mediated
-lactamase. Again, the
inoculum effects
occurred most frequently in tests with cefepime,
cefotaxime, and
ceftriaxone (Table
5). Cefepime was the agent most
dramatically
affected, with susceptibility decreasing from 96% in the
standard-inoculum
tests to only 8% of isolates inhibited by 8 µg/ml
in the higher-inoculum
tests. Inoculum effects with meropenem and/or
cefoteten occurred
in tests with more than 50% of these strains (17 of
23 isolates
for meropenem and 11 of 19 isolates for cefoteten). Even
so, the
high-inoculum MICs of meropenem exceeded 4 µg/ml for only
three
isolates. Representative results are shown in Table
4.
| |
DISCUSSION |
A pronounced inoculum effect may occur when a bacterium produces
an enzyme capable of destroying an antibiotic. When bacterial killing
and destruction of the antibiotic occur simultaneously, liberated
enzyme from dead cells reduces the external concentration of the
antibiotic (42). In an in vitro test the ability of the inoculum to influence the antibacterial activity of a -lactam drug
is determined primarily by two factors
the intrinsic activity of the
drug against the test organism and the susceptibility of the drug to
hydrolysis by the -lactamase(s) of the organism. In general, the
larger the inoculum effect is, the more susceptible the drug is to
hydrolysis by the organism's -lactamase(s).
High inocula occur in endocarditis, meningitis, septic arthritis,
osteomyelitis, abscesses, and other deep-seated infections. In
addition, stationary-phase growth, which favors -lactamase activity
and is detrimental to -lactam drug efficacy, also occurs in these
infections (41). As examples of high inocula, colony counts of 109 to 1010 CFU
per g of tissue in infective endocarditis vegetations (16) and 109 CFU per ml of cerebrospinal fluid in
meningitis (2) have been reported, and these values
significantly exceed the more modest 107 CFU per
ml used in the present study. In this context, it is pertinent to
consider the relevance of inoculum effects and of MICs determined with
higher-than-standard inocula. In support of their utility, animal
models of pneumonia have shown that antibiotics not associated with an
inoculum effect are more efficacious than those exhibiting an inoculum
effect (29). Balanced against this is the caution that it
is unwise to overlook the fact that data from animal models are subject
to variables such as the host status (e.g., neutropenic versus normal)
and the challenge organism (29, 35). Despite such
concerns, inoculum effects are accepted as relevant by some
investigators, at least to the extent that it has been proposed that
"a major inoculum effect for a compound contraindicates its use in
serious infections caused by the pathogen" (18).
In this study, the inoculum effect was most pronounced in tests with
the cephalosporins cefepime, cefotaxime, and ceftriaxone, with cefepime
being at least as affected as cefotaxime and ceftriaxone. The inoculum
effect was smallest and least common in tests with meropenem and
cefoteten. These findings are consistent with previous reports that
carbapenems and cephamycins are not inactivated by Bush group 2be
-lactamases while cephalosporins are (6). Cefepime has
been described in some reports as less prone than other cephalosporins to hydrolysis by ESBLs (26, 31). However, the inoculum
effects consistently observed with cefepime suggest that it is at least as prone to inactivation by an extensive range of ESBLs as cefotaxime and ceftriaxone, and more so than ceftazidime and aztreonam. This finding adds support to and extends findings of other investigators (14, 19, 43). To our knowledge, the clinical implications of an inoculum effect with cefepime have not been evaluated. Therefore, until there are reliable clinical data to resolve this issue, it might
be prudent for clinicians who are considering using cefepime for
therapy of serious infections caused by ESBL-producing pathogens to be
prepared to monitor patients closely for signs of treatment failure.
Piperacillin-tazobactam was less subject to an inoculum effect than the
cephalosporins and aztreonam. Inoculum effects with this agent occurred
consistently in tests with strains producing SHV-derived ESBLs but
occurred only occasionally in tests with strains producing TEM-derived
ESBLs, and only with certain TEM-derived ESBLs. As with cefepime,
clinical data are required to determine the relevance of these
findings. It is possible that piperacillin-tazobactam might have better
efficacy against pathogens that produce the TEM-derived ESBLs that
are not associated with an inoculum effect than against those that
produce other types of ESBLs. However, this issue is currently moot
because it is beyond the capability of clinical laboratories to
routinely identify the types of ESBLs encountered in patient isolates.
In standard-inoculum tests 61% (14 of 23) of the ESBL-producing
isolates from species known to produce an inducible AmpC -lactamase were susceptible to one or more of the expanded-spectrum
cephalosporins, and 96% (22 of 23) were susceptible to cefepime. With
cephalosporin MICs as low as 0.06 to 2 µg/ml for some of the
ESBL-producing isolates, but significantly higher in ESBL-negative,
derepressed mutants (internal data, Center for Research in
Antiinfectives and Biotechnology), it is clearly impossible to devise a
reliable ESBL screen for inducible AmpC-producing organisms based on
susceptibility to cephalosporins. Aztreonam is similarly inappropriate
as an indicator drug for ESBL detection in these organisms. Therefore, other approaches, such as inhibitor-based tests, must be used to detect
ESBLs in these organisms. In view of reports of the increasing
occurrence of ESBLs in Enterobacter spp. and other AmpC-producing species (8; T. Gottlieb and C. Wolfson,
Letter, J. Antimicrob Chemother. 46:330-331, 2000), the
development of such tests must be a priority.
Laboratories using NCCLS guidelines are currently required to report
susceptibility if the MICs of expanded-spectrum cephalosporin or
aztreonam for ESBL-producing isolates of species other than E. coli or Klebsiella spp. are 8 µg/ml or less. However,
ESBL-producing E. coli and Klebsiella spp. are
reported as resistant to these agents irrespective of MIC.
(-Lactamase inhibitor combinations and cephamycins are excluded from
this recommendation.) Unless there is evidence that ESBLs are
clinically less significant in organisms other than E. coli
and Klebsiella spp., it would seem prudent to extend the
reporting practice to all ESBL-producing isolates, i.e., report them
all as resistant to all penicillins, cephalosporins, and aztreonam,
irrespective of their identity.
| |
ACKNOWLEDGMENTS |
This work was supported by a grant from Astra Zeneca, Wilmington, Del.
We thank Stacey Edward for technical assistance, Patti Falk for
assistance with the preparation of the manuscript, and Christine C. Sanders, Henry D. Isenberg, and David L. Paterson for their helpful
comments. We also thank the many investigators worldwide who provided
the strains used in this study.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Center for
Research in Antiinfectives and Biotechnology, Department of Medical
Microbiology and Immunology, Creighton University School of Medicine,
Omaha, NE 68178. Phone: (402) 280-2921. Fax: (402) 280-1225. E-mail: kstaac{at}creighton.edu.
| |
REFERENCES |
| 1.
|
Bauernfeind, A.,
H. Grimm, and S. Schweighart.
1990.
A new plasmidic cefotaximase in a clinical isolate of Escherichia coli.
Infection
18:294-298[CrossRef][Medline].
|
| 2.
|
Bingen, E.,
N. Lambert-Zechovsky,
P. Mariani-Kurkdjian,
C. Doit,
Y. Aujard,
F. Fournerie, and H. Mathieu.
1990.
Bacterial counts in cerebrospinal fluid of children with meningitis.
Eur J. Clin. Microbiol. Infect. Dis.
9:278-281[CrossRef][Medline].
|
| 3.
|
Bradford, P. A.,
C. E. Cherubin,
V. Idemyor,
B. A. Rasmussen, and K. Bush.
1994.
Multiply resistant Klebsiella pneumoniae strains from two Chicago hospitals: identification of the extended-spectrum TEM-12 and TEM-10 ceftazidime-hydrolyzing -lactamases in a single isolate.
Antimicrob. Agents Chemother.
38:761-766[Abstract/Free Full Text].
|
| 4.
|
Bradford, P. A., and C. C. Sanders.
1995.
Development of test panel of -lactamases expressed in a common Escherichia coli host background for evaluation of new -lactam antibiotics.
Antimicrob. Agents Chemother.
39:308-313[Abstract/Free Full Text].
|
| 5.
|
Brun-Buisson, C.,
P. Legrand,
A. Philippon,
F. Montravers,
M. Ansquer, and J. Duval.
1987.
Transferable enzymatic resistance to third-generation cephalosporins during nosocomial outbreak of multiresistant Klebsiella pneumoniae.
Lancet
ii:302-306.
|
| 6.
|
Bush, K.,
G. A. Jacoby, and A. A. Medeiros.
1995.
A functional classification scheme for -lactamases and its correlation with molecular structure.
Antimicrob. Agents Chemother.
39:1211-1233[Free Full Text].
|
| 7.
|
Chanal, C. M.,
D. L. Sirot,
A. Petit,
R. Labia,
A. Morand,
J. L. Sirot, and R. A. Cluzel.
1989.
Multiplicity of TEM-derived beta-lactamases from Klebsiella pneumoniae strains isolated at the same hospital and relationships between the responsible plasmids.
Antimicrob. Agents Chemother.
33:1915-1920[Abstract/Free Full Text].
|
| 8.
|
De Champs, C.,
D. Sirot,
C. Chanal,
R. Bonnet,
J. Sirot, and The French Study Group.
2000.
A 1998 survey of extended-spectrum -lactamases in Enterobacteriaceae in France.
Antimicrob. Agents Chemother.
44:3177-3179[Abstract/Free Full Text].
|
| 9.
|
DuBois, S. K.,
M. S. Marriott, and S. G. B. Amyes.
1995.
TEM- and SHV-derived extended-spectrum -lactamases: relationship between selection, structure and function.
J. Antimicrob. Chemother.
35:7-22[Abstract/Free Full Text].
|
| 10.
|
French, G. L.,
K. P. Shannon, and N. Simmons.
1996.
Hospital outbreak of Klebsiella pneumoniae resistant to broad-spectrum cephalosporins and -lactam--lactamase inhibitor combinations by hyperproduction of SHV-5 beta-lactamase.
J. Clin. Microbiol.
34:358-363[Abstract/Free Full Text].
|
| 11.
|
Jacoby, G. A., and I. Carreras.
1990.
Activities of -lactam antibiotics against Escherichia coli strains producing extended-spectrum -lactamases.
Antimicrob. Agents Chemother.
34:858-862[Abstract/Free Full Text].
|
| 12.
|
Jacoby, G. A., and A. A. Medeiros.
1991.
More extended-spectrum -lactamases.
Antimicrob. Agents Chemother.
35:1697-1704[Free Full Text].
|
| 13.
|
Jarlier, V.,
M.-H. Nicolas,
G. Fournier, and A. Philippon.
1988.
Extended broad-spectrum -lactamases conferring transferable resistance to newer -lactam agents in Enterobacteriaceae: hospital prevalence and susceptibility patterns.
Rev. Infect. Dis.
10:867-878[Medline].
|
| 14.
|
Jett, B. D.,
D. J. Ritchie,
R. Reichley,
T. C. Bailey, and D. F. Sahm.
1995.
In vitro activities of various -lactam antimicrobial agents against clinical isolates of Escherichia coli and Klebsiella spp. resistant to oxyimino cephalosporins.
Antimicrob. Agents Chemother.
39:1187-1190[Abstract/Free Full Text].
|
| 15.
|
Karas, J. A.,
D. G. Pillay,
D. Muckart, and A. W. Sturm.
1996.
Treatment failure due to extended spectrum -lactamase.
J. Antimicrob. Chemother.
37:203-204[Free Full Text].
|
| 16.
|
Korzeniowski, O., and D. Kaye.
1998.
Endocarditis, p. 663-674.
In
S. L. Gorbach, J. G. Bartlett, and N. R. Blacklow (ed.), Infectious diseases, 2nd ed. W. B. Saunders Company, Philadelphia, Pa.
|
| 17.
|
Leleu, G.,
M. D. Kitzis,
J. M. Vallois,
L. Gutmann, and J. M. Decazes.
1994.
Different ratios of the piperacillin-tazobactam combination for treatment of experimental meningitis due to Klebsiella pneumoniae producing the TEM-3 extended-spectrum -lactamase.
Antimicrob. Agents Chemother.
38:195-199[Abstract/Free Full Text].
|
| 18.
|
Livermore, D. M.
1998.
-Lactamase-mediated resistance and opportunities for its control.
J. Antimicrob. Chemother.
41(Suppl. D):25-41[Abstract/Free Full Text].
|
| 19.
|
Martinez-Martinez, L.,
A. Pascual,
S. Hernandez-Alles,
D. Alvarez-Diaz,
A. I. Suarez,
J. Tran,
V. J. Benedi, and G. A. Jacoby.
1999.
Roles of -lactamases and porins in activities of carbapenems and cephalosporins against Klebsiella pneumoniae.
Antimicrob. Agents Chemother.
43:1669-1673[Abstract/Free Full Text].
|
| 20.
|
Matthew, M. A.,
A. M. Harris,
M. J. Marshall, and G. W. Ross.
1975.
The use of analytical isoelectric focusing for detection and identification of -lactamases.
J. Gen. Microbiol.
88:169-178[Medline].
|
| 21.
|
Mentec, H.,
J. M. Vallois,
A. Bure,
A. Saleh-Mghir,
F. Jehl, and C. Carbon.
1992.
Piperacillin, tazobactam, and gentamicin alone or combined in an endocarditis model of infection by a TEM-3-producing strain of Klebsiella pneumoniae or its susceptible variant.
Antimicrob. Agents Chemother.
36:1883-1889[Abstract/Free Full Text].
|
| 22.
|
National Committee for Clinical Laboratory Standards.
1997.
Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Approved standard M7-A4.
National Committee for Clinical Laboratory Standards, Villanova, Pa.
|
| 23.
|
National Committee for Clinical Laboratory Standards.
2000.
Performance standards for antimicrobial susceptibility testing; tenth informational supplement (aerobic dilution) M100-S10.
NCCLS, Wayne, Pa.
|
| 24.
|
Neu, H. C.,
N. X. Chin, and H. B. Huang.
1993.
In vitro activity and beta-lactamase stability of FK-037, a parenteral cephalosporin.
Antimicrob. Agents Chemother.
37:566-573[Abstract/Free Full Text].
|
| 25.
|
O'Callaghan, C. H.,
P. W. Muggleton, and G. W. Ross.
1968.
Effects of beta-lactamase from gram-negative organisms on cephalosporins and penicillins.
Antimicrob. Agents Chemother.
8:57-63.
|
| 26.
|
Paterson, D. L.
2000.
Recommendation for treatment of severe infections caused by Enterobacteriaceae producing extended-spectrum beta-lactamases (ESBLs).
Clin. Microbiol. Infect.
6:460-463[CrossRef][Medline].
|
| 27.
|
Paterson, D. L.,
W.-C. Ko,
A. Von Gottberg,
J. M. Casellas,
L. Mulazimoglu,
K. P. Klugman,
R. A. Bonomo,
L. B. Rice,
J. G. McCormack, and V. L. Yu.
2001.
Outcome of cephalosporin treatment for serious infections due to apparently susceptible organisms producing extended-spectrum beta-lactamases: implications for the clinical microbiology laboratory.
J. Clin. Microbiol.
39:2206-2212[Abstract/Free Full Text].
|
| 28.
|
Paterson, D. L.,
N. Singh,
T. Gayowski, and I. R. Marino.
1999.
Fatal infection due to extended-spectrum beta-lactamase-producing Escherichia coli: implications for antibiotic choice for spontaneous bacterial peritonitis.
Clin. Infect. Dis.
28:683-684[Medline].
|
| 29.
|
Pennington, J. E.
1985.
Animal models of pneumonia for evaluation of antimicrobial therapy.
J. Antimicrob. Chemother.
16:1-6[Free Full Text].
|
| 30.
|
Philippon, A.,
S. B. Redjeb,
G. Fournier, and A. B. Hassen.
1989.
Epidemiology of extended spectrum -lactamases.
Infection
17:347-354[CrossRef][Medline].
|
| 31.
|
Rahal, J. J.
2000.
Extended-spectrum beta-lactamases: how big is the problem?
Clin. Microbiol. Infect.
2(Suppl. 2):2-6[CrossRef].
|
| 32.
|
Rice, L. B.,
L. L. Carias, and D. M. Shlaes.
1994.
In vivo efficacies of -lactam--lactamase inhibitor combinations against a TEM-26-producing strain of Klebsiella pneumoniae.
Antimicrob. Agents Chemother.
38:2663-2664[Abstract/Free Full Text].
|
| 33.
|
Rice, L. B.,
E. C. Eckstein,
J. DeVente, and D. M. Shlaes.
1996.
Ceftazidime-resistant Klebsiella pneumoniae isolates recovered at the Cleveland Department of Veterans Affairs Medical Center.
Clin. Infect. Dis.
23:118-124[Medline].
|
| 34.
|
Rice, L. B.,
S. H. Willey,
G. A. Papanicolaou,
A. A. Medeiros,
G. M. Eliopoulos,
J. Robert,
C. Moellering, and G. A. Jacoby.
1990.
Outbreak of ceftazidime resistance caused by extended-spectrum -lactamases at a Massachusetts chronic-care facility.
Antimicrob. Agents Chemother.
34:2193-2199[Abstract/Free Full Text].
|
| 35.
|
Roosendaal, R.,
I. A. Bakker-Woudenberg,
M. van den Berghe-van Raffe, and M. F. Michel.
1986.
Continuous versus intermittent administration of ceftazidime in experimental Klebsiella pneumoniae pneumonia in normal and leukopenic rats.
Antimicrob. Agents Chemother.
30:403-408[Abstract/Free Full Text].
|
| 36.
|
Sambrook, J.,
E. F. Fritsch, and T. Maniatis.
1989.
Molecular cloning: a laboratory manual, 2nd ed.
Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.
|
| 37.
|
Sanders, C. C.
1993.
Cefepime: the next generation?
Clin. Infect. Dis.
17:369-379[Medline].
|
| 38.
|
Sanders, C. C.
1996.
In vitro activity of fourth generation cephalosporins against enterobacteriaceae producing extended-spectrum beta-lactamases.
J. Chemother.
8(Suppl. 2):57-62.
|
| 39.
|
Sanders, C. C.,
W. E. Sanders, Jr., and E. S. Moland.
1986.
Characterization of -lactamases in situ on polyacrylamide gels.
Antimicrob. Agents Chemother.
30:951-952[Abstract/Free Full Text].
|
| 40.
|
Sirot, D.
1995.
Extended-spectrum plasmid-mediated -lactamases.
J. Antimicrob. Chemother.
36:19-34.
|
| 41.
|
Stratton, C. W.
1991.
In vitro testing: correlations between bacterial susceptibility, body fluid levels and effectiveness of antibacterial therapy, p. 849-879.
In
V. Lorian (ed.), Antibiotics in laboratory medicine, 3rd ed. Williams & Wilkins, Baltimore, Md.
|
| 42.
|
Sykes, R. B., and M. Matthew.
1976.
The beta-lactamases of gram-negative bacteria and their role in resistance to beta-lactam antibiotics.
J. Antimicrob. Chemother.
2:115-157[Free Full Text].
|
| 43.
|
Thauvin-Eliopoulos, C.,
M. F. Tripodi,
R. C. Moellering, Jr., and G. M. Eliopoulos.
1997.
Efficacies of piperacillin-tazobactam and cefepime in rats with experimental intra-abdominal abscesses due to an extended-spectrum beta-lactamase-producing strain of Klebsiella pneumoniae.
Antimicrob. Agents Chemother.
41:1053-1057[Abstract/Free Full Text].
|
| 44.
|
Thomson, K. S.,
A. M. Prevan, and C. C. Sanders.
1996.
Novel plasmid-mediated -lactamases in Enterobacteriaceae: emerging problems for new -lactam antibiotics, p. 151-163.
In
J. S. Remington, and M. N. Swartz (ed.), Current clinical topics in infectious diseases, vol. 16. Blackwell Science, Inc., Cambridge, Mass.
|
| 45.
|
Thomson, K. S., and E. Smith Moland.
2000.
Version 2000: the new beta-lactamases of Gram-negative bacteria at the dawn of the new millennium.
Microbes Infect.
2:1225-1235[CrossRef][Medline].
|
| 46.
|
Tzouvelekis, L. S.,
E. Tzelepi,
A. F. Mentis, and N. J. Legakis.
1995.
In vitro activity of cefpirome against selected clinical enterobacterial isolates with beta-lactamase-mediated resistance.
Infection
23:384-387[CrossRef][Medline].
|
| 47.
|
Venezia, R. A.,
F. J. Scarano,
K. E. Preston,
L. M. Steele,
T. P. Root,
R. Limberger,
W. Archinal, and M. A. Kacica.
1995.
Molecular epidemiology of an SHV-5 extended-spectrum beta-lactamase in Enterobacteriaceae isolated from infants in a neonatal intensive care unit.
Clin. Infect. Dis.
21:915-923[Medline].
|
Antimicrobial Agents and Chemotherapy, December 2001, p. 3548-3554, Vol. 45, No. 12
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.12.3548-3554.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
This article has been cited by other articles:
-
Towne, T. G., Lewis, J. S. II, Herrera, M., Wickes, B., Jorgensen, J. H.
(2010). Detection of SHV-Type Extended-Spectrum Beta-Lactamase in Enterobacter Isolates. J. Clin. Microbiol.
48: 298-299
[Abstract]
[Full Text]
-
Baughman, R. P.
(2009). The Use of Carbapenems in the Treatment of Serious Infections. J Intensive Care Med
24: 230-241
[Abstract]
-
Vimont, S., Aubert, D., Mazoit, J.-X., Poirel, L., Nordmann, P.
(2007). Broad-spectrum {beta}-lactams for treating experimental peritonitis in mice due to Escherichia coli producing plasmid-encoded cephalosporinases. J Antimicrob Chemother
60: 1045-1050
[Abstract]
[Full Text]
-
Perez, F., Hujer, A. M., Hujer, K. M., Decker, B. K., Rather, P. N., Bonomo, R. A.
(2007). Global Challenge of Multidrug-Resistant Acinetobacter baumannii. Antimicrob. Agents Chemother.
51: 3471-3484
[Full Text]
-
Valeria dos Santos, K., Diniz, C. G., Coutinho, S. C., Apolonio, A. C. M., Geralda de Sousa-Gaia, L., Nicoli, J. R., Farias, L. d. M., Roque de Carvalho, M. A.
(2007). In vitro activity of piperacillin/tazobactam and ertapenem against Bacteroides fragilis and Escherichia coli in pure and mixed cultures. J Med Microbiol
56: 798-802
[Abstract]
[Full Text]
-
Wiegand, I., Geiss, H. K., Mack, D., Sturenburg, E., Seifert, H.
(2007). Detection of Extended-Spectrum Beta-Lactamases among Enterobacteriaceae by Use of Semiautomated Microbiology Systems and Manual Detection Procedures. J. Clin. Microbiol.
45: 1167-1174
[Abstract]
[Full Text]
-
Schmitt, J., Jacobs, E., Schmidt, H.
(2007). Molecular characterization of extended-spectrum beta-lactamases in Enterobacteriaceae from patients of two hospitals in Saxony, Germany. J Med Microbiol
56: 241-249
[Abstract]
[Full Text]
-
Zimhony, O., Chmelnitsky, I., Bardenstein, R., Goland, S., Hammer Muntz, O., Navon Venezia, S., Carmeli, Y.
(2006). Endocarditis Caused by Extended-Spectrum-{beta}-Lactamase-Producing Klebsiella pneumoniae: Emergence of Resistance to Ciprofloxacin and Piperacillin-Tazobactam during Treatment despite Initial Susceptibility. Antimicrob. Agents Chemother.
50: 3179-3182
[Abstract]
[Full Text]
-
Scheetz, M. H., Hurt, K. M., Noskin, G. A., Oliphant, C. M.
(2006). Applying antimicrobial pharmacodynamics to resistant gram-negative pathogens.. Am J Health Syst Pharm
63: 1346-1360
[Abstract]
[Full Text]
-
Gavin, P. J., Suseno, M. T., Thomson, R. B. Jr., Gaydos, J. M., Pierson, C. L., Halstead, D. C., Aslanzadeh, J., Brecher, S., Rotstein, C., Brossette, S. E., Peterson, L. R.
(2006). Clinical Correlation of the CLSI Susceptibility Breakpoint for Piperacillin- Tazobactam against Extended-Spectrum-{beta}-Lactamase-Producing Escherichia coli and Klebsiella Species. Antimicrob. Agents Chemother.
50: 2244-2247
[Abstract]
[Full Text]
-
Sturenburg, E., Storm, N., Sobottka, I., Horstkotte, M. A., Scherpe, S., Aepfelbacher, M., Muller, S.
(2006). Detection and Genotyping of SHV {beta}-Lactamase Variants by Mass Spectrometry after Base-Specific Cleavage of In Vitro-Generated RNA Transcripts. J. Clin. Microbiol.
44: 909-915
[Abstract]
[Full Text]
-
Paterson, D. L., Bonomo, R. A.
(2005). Extended-Spectrum {beta}-Lactamases: a Clinical Update. Clin. Microbiol. Rev.
18: 657-686
[Abstract]
[Full Text]
-
Jacoby, G. A., Munoz-Price, L. S.
(2005). The New {beta}-Lactamases. NEJM
352: 380-391
[Full Text]
-
Kang, C.-I., Pai, H., Kim, S.-H., Kim, H.-B., Kim, E.-C., Oh, M.-d., Choe, K.-W.
(2004). Cefepime and the inoculum effect in tests with Klebsiella pneumoniae producing plasmid-mediated AmpC-type {beta}-lactamase. J Antimicrob Chemother
54: 1130-1133
[Abstract]
[Full Text]
-
Pai, H., Hong, J. Y., Byeon, J.-H., Kim, Y.-K., Lee, H.-J.
(2004). High Prevalence of Extended-Spectrum {beta}-Lactamase-Producing Strains among Blood Isolates of Enterobacter spp. Collected in a Tertiary Hospital during an 8-Year Period and Their Antimicrobial Susceptibility Patterns. Antimicrob. Agents Chemother.
48: 3159-3161
[Abstract]
[Full Text]
-
Wiegand, I., Burak, S.
(2004). Effect of inoculum density on susceptibility of Plesiomonas shigelloides to cephalosporins. J Antimicrob Chemother
54: 418-423
[Abstract]
[Full Text]
-
Stearne, L. E. T., van Boxtel, D., Lemmens, N., Goessens, W. H. F., Mouton, J. W., Gyssens, I. C.
(2004). Comparative Study of the Effects of Ceftizoxime, Piperacillin, and Piperacillin-Tazobactam Concentrations on Antibacterial Activity and Selection of Antibiotic-Resistant Mutants of Enterobacter cloacae and Bacteroides fragilis In Vitro and In Vivo in Mixed-Infection Abscesses. Antimicrob. Agents Chemother.
48: 1688-1698
[Abstract]
[Full Text]
-
Queenan, A. M., Foleno, B., Gownley, C., Wira, E., Bush, K.
(2004). Effects of Inoculum and {beta}-Lactamase Activity in AmpC- and Extended-Spectrum {beta}-Lactamase (ESBL)-Producing Escherichia coli and Klebsiella pneumoniae Clinical Isolates Tested by Using NCCLS ESBL Methodology. J. Clin. Microbiol.
42: 269-275
[Abstract]
[Full Text]
-
Canton, R., Loza, E., Del Carmen Conejo, M., Baquero, F., Martinez-Martinez, L.
(2003). Quality Control for {beta}-Lactam Susceptibility Testing with a Well-Defined Collection of Enterobacteriaceae and Pseudomonas aeruginosa Strains in Spain. J. Clin. Microbiol.
41: 1912-1918
[Abstract]
[Full Text]
-
Coudron, P. E., Hanson, N. D., Climo, M. W.
(2003). Occurrence of Extended-Spectrum and AmpC Beta-Lactamases in Bloodstream Isolates of Klebsiella pneumoniae: Isolates Harbor Plasmid-Mediated FOX-5 and ACT-1 AmpC Beta-Lactamases. J. Clin. Microbiol.
41: 772-777
[Abstract]
[Full Text]
-
Leverstein-van Hall, M. A., Fluit, A. C., Paauw, A., Box, A. T. A., Brisse, S., Verhoef, J.
(2002). Evaluation of the Etest ESBL and the BD Phoenix, VITEK 1, and VITEK 2 Automated Instruments for Detection of Extended-Spectrum Beta-Lactamases in Multiresistant Escherichia coli and Klebsiella spp.. J. Clin. Microbiol.
40: 3703-3711
[Abstract]
[Full Text]
Top
Abstract
Introduction
