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Antimicrobial Agents and Chemotherapy, October 2001, p. 2831-2837, Vol. 45, No. 10
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.10.2831-2837.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Activity of Ertapenem (MK-0826) versus
Enterobacteriaceae with Potent
-Lactamases
David M.
Livermore,*
Karen J.
Oakton,
Michael W.
Carter, and
Marina
Warner
Antibiotic Resistance Monitoring and
Reference Laboratory, Central Public Health Laboratory, London NW9
5HT, United Kingdom
Received 30 January 2001/Returned for modification 8 May
2001/Accepted 13 July 2001
 |
ABSTRACT |
Ertapenem (MK-0826; L-749,345), a new carbapenem with a long serum
half-life, was tested, in vitro, against 
-lactamase-producing bacteria. The new compound had a MIC at which 90% of the isolates were
inhibited of 0.06 µg/ml for extended-spectrum -lactamase (ESBL)-producing klebsiellas, compared with 0.5 µg/ml for imipenem, 16 µg/ml for cefepime, and >128 µg/ml for ceftazidime and
piperacillin-tazobactam. MICs of ertapenem for AmpC-derepressed mutant
Enterobacteriaceae were 0.015 to 0.5 µg/ml, whereas
imipenem MICs were 0.25 to 1 µg/ml and those of cefepime were 0.5 to
4 µg/ml, and resistance to ceftazidime and piperacillin-tazobactam
was generalized. Despite this good activity, the MICs of ertapenem for
ESBL-positive klebsiellas mostly were two- to fourfold above those for
ESBL-negative strains, and the MICs for AmpC-hyperproducing
Enterobacter cloacae and Citrobacter
freundii mutants exceeded those for the corresponding AmpC-basal mutants. These differentials did not increase when the
inoculum was raised from 104 to 106
CFU/spot, contraindicating significant lability.
Carbapenemase producers were also tested. The IMP-1
metallo--lactamase conferred substantial ertapenem resistance (MIC,
128 µg/ml) in a porin-deficient Klebsiella pneumoniae
strain, whereas a MIC of 6 µg/ml was recorded for its
porin-expressing revertant. SME-1 carbapenemase was associated with an
ertapenem MIC of 2 µg/ml for Serratia marcescens S6,
compared with <0.03 µg/ml for Serratia strains
lacking this enzyme. In summary, ertapenem had good activity against
strains with potent -lactamases, except for those with known carbapenemases.
| |
INTRODUCTION |
Imipenem and meropenem retain
activity against bacteria with extended-spectrum -lactamases (ESBLs)
and those that hyperproduce AmpC type -lactamases and against
Klebsiella oxytoca strains that hyperproduce the K1 enzyme
(16). They also retain activity against strains with many
less-frequent cephalosporinases, such as the PER and CTX-M
enzymes. This activity gives these carbapenem drugs major
advantages over cephalosporins, since potent -lactamases are
becoming increasingly prevalent. In recent surveys, ESBLs were found in
23 to 25% of klebsiellas from European intensive care units (2,
19); moreover, Klebsiella strains with multiple ESBLs
are increasingly seen (10). AmpC -lactamases are
chromosomal and ubiquitous in Enterobacter spp.,
Citrobacter freundii, Morganella morganii, and
Serratia spp., where they give resistance to
oxyimino-aminothiazolyl cephalosporins if they are hyperproduced as a
consequence of mutation (16); in addition AmpC genes can
escape to plasmids, spreading resistance into further species
(20). Hyperproduction of the K1 enzyme is seen in an
increasing proportion of K. oxytoca isolates in European
intensive care units (2, 11).
The stability of imipenem and meropenem in the presence of potent
-lactamases makes the carbapenems an attractive class for further development (9). Ertapenem (MK-0826, L-749,345)
(15) is a new analogue in the class, notable for a long
serum half-life (ca. 4 h). We evaluated its activity against
strains with potent cephalosporin-hydrolyzing -lactamases and
against Enterobacteriaceae with class A and B -lactamases
that confer resistance to imipenem. The latter enzymes are rare and
largely restricted to nonfermenters but may represent a future problem
in Enterobacteriaceae too (17, 18).
| |
MATERIALS AND METHODS |
Bacteria.
The Klebsiella pneumoniae and
K. oxytoca isolates were collected from intensive care unit
patients in western and southern Europe during a survey undertaken in
1994 (19). They included 181 klebsiellas inferred to have
ESBLs on the basis of ceftazidime MIC/ceftazidime plus clavulanate MIC
ratios 
16. SHV-derived ESBLs in these isolates were typed by
isoelectric focusing and PCR-single-strand conformation polymorphism
(27); TEM variants were typed by isoelectric focusing and
PCR-restriction fragment length polymorphism (26). A few
blaSHV and
blaTEM genes were sequenced (26,
27). Also included, from the same survey (19), were
seven Klebsiella isolates with AmpC -lactamases and 19 K. oxytoca isolates that hyperproduced K1 -lactamase.
Twenty-five K. oxytoca and 25 K. pneumoniae
isolates without potent -lactamase types were included as controls;
these were susceptible to extended-spectrum cephalosporins at 
2
µg/ml and gave ceftazidime MIC/ceftazidime plus clavulanate MIC
ratios 4.
To assess interactions with inducible and derepressed chromosomal
-lactamases, isogenic mutant series of Enterobacter
cloacae, C. freundii, Serratia
marcescens, M. morganii, and Proteus
vulgaris were tested (3, 25). Most series comprised a
-lactamase-inducible isolate and its -lactamase-derepressed and
-basal mutants, but some lacked -lactamase-inducible parent strains,
having been derived from derepressed isolates. To assess the effect of
carbapenemases, the antibiotics were tested against S. marcescens S6, with the SME-1 enzyme (class A) (21,
25), and against K. pneumoniae K4181, a clinical
isolate from Singapore with the IMP-1 metallo--lactamase and loss of
a 39-kDa porin (14). Escherichia coli ATCC
25922 was a general control.
Susceptibility tests.
MICs were determined by National
Committee for Clinical Laboratory Standards (NCCLS) agar dilution
methodology (22). In some experiments the inocula were
adjusted to 104 and 106
CFU/spot to investigate inoculum effects. The drugs tested were ertapenem and imipenem (Merck, Rahway, N.J.), ceftazidime
(GlaxoSmithKline, Stevenage, United Kingdom), cefepime (Bristol-Myers
Squibb, Hounslow, United Kingdom), and piperacillin and
piperacillin-tazobactam (Wyeth, Taplow, United Kingdom). Tazobactam was
used at 4 µg/ml. In a few experiments, MICs were redetermined with
E-tests (AB Biodisk, Solna, Sweden) on Mueller-Hinton agar, in
accordance with the manufacturer's directions.
| |
RESULTS |
MICs for klebsiellas in relation to -lactamase
types.
MIC distributions for the klebsiellas with ESBLs, AmpC
enzymes, or hyperproduction of the K1 enzyme are illustrated in Table 1. The MIC
at which 50% of the isolates were inhibited
(MIC50) and MIC90 of
ertapenem for the ESBL producers were 0.03 and 0.06 µg/ml,
respectively, and were lower than those for any isolate compared, with the new compound about four- to eightfold more active than imipenem and with both these carbapenems considerably more
active than any other drug compared. Despite these favorable results, the MICs of ertapenem for ESBL producers were about fourfold above those for nonproducers, which were inhibited by ertapenem at 0.06 µg/ml or less. MICs of ertapenem for three producers were 1 µg/ml
or more, although always less than 16 µg/ml. MICs for these
three isolates were redetermined with E-tests, which gave values 1 dilution below those found by agar dilution (not shown).
Imipenem had a MIC
50 of 0.125 µg/ml for both
ESBL producers and nonproducers and had a MIC
90
only 1 dilution higher for ESBL
producers than for nonproducers (0.5 versus 0.25 µg/ml). An imipenem
MIC of 1 or 2 µg/ml was recorded
for five ESBL producers, whereas
MICs for nonproducers were universally
0.5 µg/ml or less. The
MICs of the cephalosporins for ESBL producers
and nonproducers
were much more stratified than were those of the
carbapenems (Table
1). Thus, the MIC
50 of
ceftazidime for ESBL producers was 64
µg/ml, whereas that for
nonproducers was 0.25 µg/ml. For cefepime,
the
MIC
50 and MIC
90 for ESBL
producers were 2 and 8 µg/ml, respectively,
compared with 0.06 and
0.12 µg/ml for ESBL-negative
K. pneumoniae and 0.03 and 0.06 µg/ml for ESBL-negative
K. oxytoca. MICs of
piperacillin exceeded 64 µg/ml for the huge majority (93%) of
ESBL
producers, whereas MICs for most nonproducers were from 4
to 16 µg/ml. Tazobactam, at 4 µg/ml, lowered the MICs of piperacillin
for
virtually all the isolates, ESBL producing or not. The distribution
of
MICs of piperacillin-tazobactam for ESBL producers was bimodal,
with
peaks at 8 and >256 µg/ml and with 69.5% of the producers
susceptible at the NCCLS breakpoint (
22) of 16 plus 4 µg/ml.
MICs for the 7 klebsiellas with AmpC enzymes are shown in Table
1, as
are those for the 19
K. oxytoca isolates that hyperproduced
the K1 enzyme. MICs of ertapenem for the AmpC producers were two-
to
fourfold higher than those for the control klebsiellas but
remained
0.06 µg/ml, whereas the MICs of imipenem for the AmpC
producers
were no higher than those for the control strains. Production
of AmpC
enzymes was associated with high-level resistance (MICs,
mostly
32
mg/ml) to ceftazidime, piperacillin, and piperacillintazobactam
and
with MICs of cefepime raised to 0.125 to 0.5 µg/ml, compared
with
0.03 to 0.06 µg/ml for control
strains.
The MIC
50s of both carbapenems were raised by
only about 1 dilution for
K. oxytoca strains that
hyperproduced the K1
-lactamase:
to 0.25 µg/ml for imipenem and
0.015 µg/ml for ertapenem. Hyperproduction
of the K1 enzyme was
associated with high-level resistance (MICs,
mostly
64 µg/ml) to
piperacillin and piperacillin-tazobactam
and with cefepime and
ceftazidime MICs raised to 0.25 to 4 µg/ml.
Activity against chromosomal -lactamase expression mutants.
MICs for AmpC -lactamase inducibility variants of E. cloacae, C. freundii, M. morganii, and S. marcescens are shown in Table 2,
together with data for P. vulgaris mutants varying in
expression of their class A chromosomal -lactamase. Ertapenem
MICs for AmpC-derepressed E. cloacae and C. freundii mutants were up to 128-fold above the exquisitely low
values for the corresponding AmpC-basal mutants but never exceeded 0.5 µg/ml. AmpC-inducible E. cloacae and C. freundii mostly were more susceptible than their derepressed
mutants but less susceptible than their -lactamase-basal mutants,
implying that inducible -lactamase also gave slight protection
against ertapenem. MICs of ertapenem for M. morganii,
S. marcescens, and P. vulgaris variants were
unrelated to enzyme expression, being equal (±1 dilution) for
-lactamase-inducible, -derepressed, and -basal organisms within a
mutant series.
Imipenem MICs were unrelated to AmpC expression for all species,
including
E. cloacae and
C. freundii.
Derepression of AmpC
raised the MICs of cefepime by up to 64-fold for
E. cloacae and
C. freundii, but the MICs for
derepressed mutants never exceeded
2 µg/ml; derepression had little
effect on the cefepime MICs for
S. marcescens,
M. morganii, and
P. vulgaris. Derepression, but
not
inducible expression, was associated with resistance to piperacillin
and, except in
S. marcescens, to ceftazidime. Tazobactam, 4 µg/ml,
reversed piperacillin resistance for derepressed
P. vulgaris and
M. morganii mutants, not for other
species.
Inoculum effects.
MICs were determined with inocula of
104 and 106 CFU/spot for
selected ESBL-producing klebsiellas and controls and for
AmpC-derepressed and -inducible Enterobacteriaceae (Table
3). The maximum inoculum effect with
ertapenem for an ESBL producer was eightfold, and most effects were
fourfold or less; effects of a similar magnitude were seen for the
ESBL-negative klebsiellas used as controls. Inoculum effects with
imipenem were slightly greater than those with ertapenem and, again,
were unrelated to ESBL production. A much greater differential was seen
with cefepime, which typically had 8- to 128-fold inoculum effects for
ESBL producers, compared with 2- to 4-fold effects for nonproducers.
Most ESBL producers were resistant (MICs, >16 µg/ml) to piperacillin
and ceftazidime even at low inocula, precluding calculation of
meaningful inoculum effect ratios. The magnitude of the inoculum
effects with piperacillin-tazobactam was highly variable. Uniquely
among the compounds tested, piperacillin had substantial (8- to
16-fold) inoculum effects for the ESBL-negative klebsiellas, presumably
because these have chromosomal LEN, SHV, or K1 enzymes, which are
active against piperacillin (16; G. S. Babini and
D. M. Livermore, Letter, Antimicrob. Agents Chemother. 44:22302000).
The inoculum effects of ertapenem and imipenem for AmpC-derepressed
strains were 2- to 4-fold, whereas ratios of 8- to 32-fold
were seen
for cefepime; AmpC-derepressed organisms mostly were
resistant to
piperacillin and ceftazidime at low inocula, precluding
calculation of
meaningful inoculum effect ratios. Inoculum effects
for the
AmpC-inducible control strains were widely scattered for
all the
compounds; this observation is subject to the caveat that
the
increased MICs with higher inocula may have reflected the
selection of
derepressed mutants, not growth of the majority
population.
Activity against carbapenemase producers.
K.
pneumoniae K4181, with the IMP-1 enzyme and lacking a 39-kDa porin
(14), was highly resistant (MIC, >32 µg/ml) to all the
-lactams tested, including both carbapenems (Table
4). The MICs of imipenem and ertapenem
fell to 2 and 6 µg/ml, respectively, for a variant that retained the
carbapenemase but that had regained expression of the porin. This
variant remained highly resistant to the noncarbapenem drugs
compared. S. marcescens S6, with the SME-1 enzyme,
was resistant to imipenem (MIC, 32 µg/ml) and had reduced
susceptibility to ertapenem (MIC, 2 µg/ml) compared with typical
S. marcescens strains such as S2 and S7 in Table 2. This strain retained good susceptibility to the other drugs compared.
| |
DISCUSSION |
Established carbapenems have a deserved reputation for
activity against ESBL-producing and AmpC-derepressed
Enterobacteriaceae, with resistance arising only when these
mechanisms are combined with impermeability (5, 16, 17).
We examined whether ertapenem shared this favorable behavior and tested
its activity against strains with molecular class A and B carbapenemases.
Ertapenem was strongly active against ESBL-producing
Klebsiella isolates and AmpC-derepressed
Enterobacteriaceae, with MICs mostly ca. 0.03 to 0.12 µg/ml and always 4 µg/ml. Nevertheless, ertapenem was ca.
fourfold less active against ESBL producers than against nonproducers
(Table 1); moreover, E. cloacae and C. freundii
strains that hyperproduced AmpC enzymes were less susceptible than
their AmpC-basal mutants (Table 2). These data suggest that ertapenem
is slightly less stable in the presence of -lactamase than
imipenem and meropenem, which retain full activity against ESBL
producers and against AmpC-hyperproducing E. cloacae and
C. freundii (2, 3, 16, 25). To investigate this
aspect, ESBL-producing and AmpC-derepressed strains were examined for
inoculum effects. In general, the effects of -lactamase lability on
MICs become more apparent as the inoculum is raised, as seen here with
cefepime against ESBL producers and with piperacillin against control
klebsiellas. The inoculum effects observed with ertapenem were small,
less even than with imipenem, and substantial lability in the presence
of ESBLs and AmpC enzymes could therefore be discounted. The
slightly increased MICs of ertapenem for some ESBL producers and
AmpC-derepressed strains may reflect other factors. We note by analogy
that the MICs of cefoxitin for many ESBL-positive klebsiellas exceed
those for ESBL-negative strains (2, 19) but that
ESBL-coding plasmids do not raise the MICs of cefoxitin for E. coli transconjugants (13).
AmpC-inducible E. cloacae and C. freundii were
more susceptible than their derepressed mutants to ertapenem but less
susceptible than the corresponding AmpC- basal mutants. This
observation implies that ertapenem, like biapenem and sanfetrinem
(3, 6) but unlike imipenem (25), is not a
strong inducer of AmpC enzymes in MIC tests. Confirmation of this
inference must, however, await direct induction assays.
Acquired carbapenemases are rare but are increasingly being reported,
mostly from nonfermenters but occasionally from
Enterobacteriaceae. Interest has centered on the IMP and VIM
metallo--lactamases, which belong to molecular class B, but
carbapenemase activity has also been found in a few class A and D
enzymes. IMP enzymes are scattered in Pseudomonas aeruginosa
and Serratia in Japan and have been found also in isolates
from Canada, China, Italy, Hong Kong, and Singapore, (7, 12, 18,
24); VIM enzymes have been found in P. aeruginosa
isolates from widely scattered sites across Eurasia (18).
Class D -lactamases with carbapenemase activity have been found in
Acinetobacter spp. worldwide but not in other genera
(1, 4, 8); class A -lactamases able to hydrolyze
carbapenems have been found in tiny numbers of Serratia and
Enterobacter spp. from Europe and North America
(18). K. pneumoniae K4181 with IMP-1
-lactamase and lacking a 39-kDa porin was resistant to all
-lactams tested, including ertapenem. Resistance to carbapenems, but
not to other antibiotics, was reduced when expression of the porin was
restored. The view that IMP enzymes require impermeability (or some
other factor) to confer carbapenem resistance is supported by the
observations that imipenem MICs for E. coli transconjugants
with the IMP-1 enzyme are only ca. 2 µg/ml (14, 23) and
that many blaIMP+P.
aeruginosa isolates express resistance to ceftazidime but not to
imipenem (24). S. marcescens S6, with the SME-1
enzyme (21), was resistant to imipenem and had reduced
susceptibility to ertapenem (MIC, 2 µg/ml) as well as to meropenem
(MIC, 2 µg/ml [3, 21]). It is unclear whether these
MICs equate to clinical resistance; they are ca. 32-fold higher than
those for typical S. marcescens strains but still below the
NCCLS breakpoints for imipenem and meropenem, which are as follows:
susceptible, 4 µg/ml; resistant, 16 µg/ml (22).
Provisional NCCLS MIC breakpoints for ertapenem are identical (NCCLS
summary minutes of the meeting of the Subcommittee on Antimicrobial
Susceptibility Testing, 7 to 9 June 1998, p. 15-16) but await formal
confirmation and ratification.
In summary, ertapenem has acceptable stability in the presence of AmpC
and ESBLs, which are increasingly widespread in current isolates. In
the future, ertapenem and other carbapenems may be threatened by the
spread of IMP-1 and other metallo--lactamases. The magnitude of this
threat is likely to depend on the level of usage, and suitable
surveillance in warranted. Spread of SME-1-like enzymes seems a lesser
hazard, as none has ever been shown to be transferable among bacteria.
| |
ACKNOWLEDGMENT |
We are grateful to Merck & Co. for financial support.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Antibiotic
Resistance Monitoring and Reference Laboratory, Central Public Health
Laboratory, 61 Colindale Ave., London NW9 5HT, United Kingdom.
Phone: 44 (0)20-8200-4400. Fax: 44 (0)20-8358-3292. E-mail:
DLivermore{at}phls.org.uk.
| |
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Antimicrobial Agents and Chemotherapy, October 2001, p. 2831-2837, Vol. 45, No. 10
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.10.2831-2837.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
