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International Journal of Medical Microbiology
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Mini Review
Resistance to cephalosporins and carbapenems in Gram-negative
bacterial pathogens
Yvonne Pfeifer, Angela Cullik, Wolfgang Witte ∗
Robert Koch-Institute, Nosocomial Infections, Wernigerode Branch, Burgstr. 37, 38855 Wernigerode, Germany
a r t i c l e
Keywords:
Antibiotic resistance
Enterobacteriaceae
ESBL
Carbapenemases
i n f o
a b s t r a c t
During the past 15 years, emergence and dissemination of ␤-lactam resistance in nosocomial Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii, became a serious problem worldwide.
Especially the increasing resistance to 3rd and 4th generation cephalosporins and carbapenems is of
particular concern. Gram-negative bacteria pursue various molecular strategies for development of resistance to these antibiotics: (a) generation of extended-spectrum ␤-lactamases (ESBL) according to the
original definition due to extension of the spectrum of already widely disseminated plasmid-encoded
␤-lactamases by amino acid substitution; (b) acquisition of genes encoding ESBL from environmental
bacteria as, for instance the CTX-M-type ␤-lactamases from Kluyvera spp.; (c) high-level expression of
chromosome-encoded ␤-lactamase (bla) genes as blaOXA or blaampC genes due to modifications in regulatory genes, mutations of the ␤-lactamase promoter sequence as well as integration of insertion sequences
containing an efficient promoter for intrinsic bla genes; (d) mobilization of bla genes by incorporation in
integrons and horizontal transfer into other Gram-negative species such as the transfer of the ampC gene
from Citrobacter freundii to Klebsiella spp.; (e) dissemination of plasmid-mediated carbapenemases as KPC
and metallo-␤-lactamases, e.g. VIM and IMP; (f) non-expression of porin genes and/or efflux pump-based
antibiotic resistance.
This mini-review summarizes the historical emergence of ␤-lactam resistance and ␤-lactamases
as major resistance mechanism in enteric bacteria, and also highlights recent developments such as
multidrug- and carbapenem resistance.
© 2010 Elsevier GmbH. All rights reserved.
Introduction
Gram-negative bacteria possess resistance mechanisms affecting antibiotics of different classes such as tetracyclines, aminoglycosides, and cotrimoxazole. However, broad-spectrum resistance
to ␤-lactams and to fluorquinolones are today of the utmost significance. Ciprofloxacin is a very popular fluorquinolone for treatment
of nosocomial infections, e.g. urinary tract infections. The frequent
resistance to ciprofloxacin in Enterobacteriaceae is due to mutations
in target genes. In recent years, a new resistance mechanism is
increasingly observed. The plasmid-mediated qnr genes code for
pentapeptide-repeat proteins protecting the type II topoisomerase
from quinolones. This qnr mechanism causes low-level resistance
to fluorquinolones but favours and complements additional resistance mechanisms (Martinez-Martinez et al., 2008). Because of its
occurrence and transferability in many enterobacterial species the
analysis of dissemination of qnr genes demands attention.
∗ Corresponding author. Tel.: +49 3943 679 246; fax: +49 3943 679 317.
E-mail address: [email protected] (W. Witte).
Besides fluorquinolones, ␤-lactam antibiotics are most frequently applied in treatment of bacterial infections. The large
number of natural, semisynthetic and synthetic ␤-lactam antibiotics can be subdivided into 6 different structural subtypes:
(i) penams (e.g. benzylpenicillin, ampicillin);
(ii) cephems which include classical cephalosporins, 2nd generation cephalosporins (e.g. cefotiam, cefuroxime), and also
representatives of 3rd generation cephalosporins (e.g. cefotaxime, ceftazidime);
(iii) cephamycins as 7-␣-methoxy cephalosporins (e.g. cefoxitin);
(iv) monobactams as monocyclic molecules (e.g. aztreonam);
(v) penems with a 2,3-double bond in the fused thiazoline ring
(e.g. faropenem); and
(vi) carbapenems (e.g. imipenem) with an unsaturated fused 5membered ring differing from penem structure by possession
of a carbon atom at position 1.
In the early 1950s, enteric bacteria that mediated resistance
to the first penicillins attracted attention. In general, resistance of
bacteria against ␤-lactam antibiotics relies on 3 basic principles:
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Please cite this article in press as: Pfeifer, Y., et al., Resistance to cephalosporins and carbapenems in Gram-negative bacterial pathogens. Int. J.
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Fig. 1. Proportion of invasive isolates of Escherichia coli with resistance to third-generation cephalosporins in 2008 (http://www.rivm.nl/earss/). * These countries did not
report any data or reported less than 10 isolates.
(i) possession of an altered or acquired penicillin binding protein
(PBP) with low affinity for ␤-lactams (e.g. PBP2a in methicillinresistant Staphylococcus aureus);
(ii) efflux pumps that additionally use ␤-lactams as substrates (e.g.
the mex system in Pseudomonas aeruginosa);
(iii) ␤-lactamases which cleave the amide bond of the ␤-lactam
ring, thus inactivating the antibiotic agent.
The introduction of 3rd generation cephalosporins, which
started with cefotaxime 30 years ago, was a milestone in antimicrobial chemotherapy. Undoubtedly as a consequence of selective
pressure exerted by these new cephalosporins, resistance in enterobacterial species emerged a few years later. At that time, 2 main
causes were specified:
• expansion of the substrate spectrum of broad-spectrum TEMtype and SHV-type ␤-lactamases which were already widely
disseminated due to plasmid location of these genes (Jarlier et
al., 1988; Sirot et al., 1988),
• constitutive high-level expression of the intrinsic ampC gene,
coding for a cephamycinase (cefoxitin as phenotypical indicator
substrate) in species with an efficient ampC promoter such as
Fig. 2. Proportion of invasive isolates of Klebsiella pneumoniae resistant to carbapenems in 2008 (http://www.rivm.nl/earss/). * These countries did not report any data or
reported less than 10 isolates.
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3
Table 1
Modified classification scheme of ␤-lactamases (according to Ambler, 1980).
␤-lactamase-class
␤-lactamases
Important examples
Broad-spectrum
␤-lactamases
TEM-1, TEM-2 SHV-1,
SHV-11
ESBL TEM-type
TEM-3, TEM-52
ESBL SHV-type
SHV-5, SHV-12
ESBL CTX-M-type
CTX-M-1, CTX-M-15
Carbapenemases
KPC, GES, SME
AmpC cephamycinases
(chromosomal-encoded)
AmpC
Enterobacter spp.
Citrobacter spp.
cephamycins (cefoxitin),
3rd gen. cephalosporins
AmpC cephamycinases
(plasmid-encoded)
CMY, DHA, MOX FOX,
ACC,
Enterobacteriaceae
cephamycins (cefoxitin),
3rd gen. cephalosporins
Broad-spectrum
␤-lactamases
OXA-1, OXA-9
ESBL OXA-type
OXA-2, OXA-10
penicillins, 3rd gen.
cephalosporins
Carbapenemases;
Carbapenemases
OXA-48;
OXA-23,-24,-58
ampicillin, imipenem;
all ␤-lactamsc
Metallo-␤-lactamases
(Carbapenemases)
VIM IMP
A
Serine-␤-lactamases
C
D
Metallo-␤-lactamases
a
b
c
B
Preferential occurrence
Important phenotypical
resistance traitsa
ampicillin, cephalotin
Enterobacteriaceae and
nonfermentersb
penicillins, 3rd gen.
cephalosporins
all ␤-Lactamsc
Enterobacteriaceae;
A. baumannii
Enterobacteriaceae and
nonfermenters
oxacillin, ampicillin
cephalotin
all ␤-lactamsc
Characteristical resistances that are partially used used for diagnostic purposes;
Broad-spectrum ␤-lactamase TEM-1 frequently occurs in nonfermenters (P. aeruginosa, A. baumannii);
Broad hydrolytic spectrum including carbapenems.
Citrobacter freundii, Enterobacter cloacae, and Serratia marcescens
(Sanders and Sanders, 1988).
Since the early 1990s, further ␤-lactamase-related resistance
mechanisms were discovered. Particularly significant was the
mobilisation of genes coding for enzymes with ESBL activity from the environmental bacterial genus Kluyvera which led
to the rise of the CTX-M enzyme family in Enterobacteriaceae
(Bonnet, 2004). Cephalosporin resistance in E. coli can also be
mediated by hyperproduction of AmpC ␤-lactamase caused by promoter mutations increasing the ampC transcription rate (Caroff
et al., 2000). The introduction of carbapenems in antimicrobial
chemotherapy resulted in emergence of carbapenem hydrolyzing
␤-lactamases (carbapenemases); first in P. aeruginosa and Acinetobacter spp., later in Enterobacteriaceae (Bush, 1998). At present,
various ␤-lactamases are widespread in nearly every Gramnegative pathogenic species. Often, these enzymes are responsible
for therapy failure because of mediating multidrug-resistance.
The prevalence rates of ␤-lactam resistance in Gramnegative pathogens vary significantly in European countries.
Figs. 1 and 2 display the frequency of resistance to 3rd generation
cephalosporins in invasive E. coli as well as the frequency of carbapenem resistance in invasive Klebsiella pneumoniae, respectively
(EARSS data, http://www.rivm.nl/earss/).
A general view of the multitudinous number of ␤-lactamases
is given by classification schemes: Already in 1980, Ambler (1980)
recognized that there are 2 major groups of enzymes: one with
serine in its active site (class A), and another one which needs a
bivalent cation, preferentially zinc for hydrolysis (class B, metallo␤-lactamases). The group of serine-␤-lactamases was expanded
with recognition of class C enzymes (Jaurin and Grundström, 1981)
and class D enzymes (Ouellette et al., 1987). In 1995 Bush, Jacoby
and Medeiros proposed another functional classification scheme
of beta-lactamases which became widely used (Bush et al., 1995).
Table 1 displays the basic principle of ␤-lactamase classification
according to Ambler.
Resistance to cephalosporins: the “classical” ESBL
The major cause of 3rd generation cephalosporin resistance in
Enterobacteriaceae are ESBL enzymes of Ambler class A. Of special relevance are variants of broad-spectrum ␤-lactamases TEM-1,
TEM-2, and SHV-1 that are generated by mutations which extend
their substrate specificity to 3rd and 4th generation cephalosporins,
in particular to cefotaxime, ceftriaxone, and ceftazidime. These ␤lactamases exhibit a wide range of amino acid substitutions leading
to extended substrate specificity. These mutations affect the recognition of substrates and the rates of formation and hydrolysis of
the acyl–enzyme complex. There is sufficient evidence that class
A ␤-lactamases perform several conformational changes induced
by substrate binding and substrate reaction. In parallel, most substrates undergo chemical rearrangements triggered by the enzyme
attack which can lead to more complex kinetics. The interplay of
both processes finally results in extended substrate spectrum and
in different rates of hydrolysis for different cephalosporins (for
summary see also Raquet et al., 1995; Page, 2008). At present,
174 TEM-1 and TEM-2 variants and 119 SHV-1 variants have
been recorded (http://www.lahey.org/Studies on 5th of May 2010,
not yet released types are excluded). The first ESBL types were
described in Central Europe and France during the 1980s (Paterson
and Bonomo, 2005). At this time ESBL were most often associated
with nosocomial outbreaks in intensive care units due to particular strains of K. pneumoniae. This situation changed when ESBL
emerged in E. coli leading to a complex epidemiological situation
which involves different clones of E. coli, a variety of ESBL and different genetic elements carrying blaESBL genes, respectively (Pitout et
al., 2005; Rodriguez-Bano et al., 2004; Branger et al., 2005; Machado
et al., 2005; Jeong et al., 2004).
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Table 3
Frequency of ESBL types in nosocomial E. coli from Germany.
Table 2
Classification and evolution of CTX-M-type ESBL.
CTX-M group
CTX-M-1-type ESBL
Probable natural
reservoir and
precursor gene
Selected examples
of CTX-M types in
Enterobacteriaceae
K. ascorbata
kluA1-11 genes
→ CTX-M-1
→ CTX-M-3
→ CTX-M-15a
→ CTX-M-23a
→ CTX-M-28a
→ CTX-M-32a
→ CTX-M-54a
→ CTX-M-58a
CTX-M-2-type ESBL
K. ascorbata
kluA1-11 genes
→ CTX-M-2
→ CTX-M-35a
→ CTX-M-42a
CTX-M-9-type ESBL
K. georgiana
kluG1 gene
→ CTX-M-14
→ CTX-M-16a
→ CTX-M-19a
→ CTX-M-27a
CTX-M-8-type ESBL
K. georgiana
kluG1 gene
→ CTX-M-8
→ CTX-M-40
→ CTX-M-63
CTX-M-25-type ESBL
K. georgiana
kluG1 gene
→ CTX-M-25
→ CTX-M-26
→ CTX-M-41
2004
2008
No. of strains
No. of hospitals
TEM type
SHV type
CTX-M type
n = 49
n = 29
n=7
n=2
n = 40 (81%)
No. of strains
No. of hospitals
TEM type
SHV type
CTX-M type
n = 154
n = 150
n=6
n=3
n = 143 (93%)
CTX-M-1
CTX-M-2
CTX-M-3
CTX-M-9
CTX-M-14
CTX-M-15
n = 10
n=2
n=7
n=7
n=2
n = 11 (27.5%)
CTX-M-1
CTX-M-2
CTX-M-3
CTX-M-9
CTX-M-14
CTX-M-15
n = 50
n=4
n=1
n=2
n = 10
n = 76 (53%)
Other types of ESBL of Ambler class A enzymes are naturally
able to hydrolyze 3rd generation cephalosporins and/or several carbapenems such as CTX-M, VEB, GES and IBC, PER, TLA, BES, and SFO
(for summary see also Paterson and Bonomo, 2005).
Although a number of genetic mechanisms have apparently been
involved in the assimilation of blaCTX-M genes, insertion sequences
ISEcp1 and ISCR1 in association with class 1 integron structures
have obviously played a prominent role in these processes (Bonnet,
2004; Eckert et al., 2004; Poirel et al., 2005).
The incorporation of a blaCTX-M gene in E. coli or Klebsiella spp.
results in cefotaxime resistance. Expansion of the hydrolytic spectrum to ceftazidime is due to mutations which mainly affect the
-loop of the enzymes (Poirel et al., 2002; Cartelle et al., 2004;
Novais et al., 2008). New CTX-M types possessing an extended
substrate spectrum can result from convergent evolution within
each blaCTX-M subgroup. This is evident for different genetic surroundings of the blaCTX-M-14 gene in E. coli from the same hospital
setting (Navarro et al., 2007). Furthermore, this can be facilitated in
mutator strains (Stepanova et al., 2008). A brief overview about origin, dissemination, and expansion of substrate spectrum of CTX-M
enzymes is given in Table 2.
Recent emergence and origin of CTX-M-type ESBL
Dissemination of CTX-M genes
The description of the first CTX-M-type ESBL, namely CTXM-1, goes back to the late 1980s. Thereafter, new variants have
been increasingly reported. At present, 95 variants are assigned in
the Lahey clinic database. They are clustered into five lineages or
subgroups according to amino acid sequence similarities. Each subgroup has a natural ancestor represented by a chromosomal gene
of the different environmental Kluyvera species, especially K. ascorbata and K. georgiana (Bonnet, 2004). Very likely, the heterogeneity
of CTX-M types among clinical, enterobacterial isolates reflects
that blaCTX-M genes have been captured from different sources
within the genus Kluyvera by multiple events (Barlow et al., 2008).
In general, spread of antibiotic resistance genes like blaCTX-M
is facilitated by 3 major strategies: (a) clonal dissemination of the
bacterial strain which has acquired resistance genes; (b) spread of a
particular plasmid and/or transposon between a variety of different
strains; and (c) translocation of resistance genes between different
mobile genetic elements.
At first sight, one would assume that the European-wide rise of
CTX-M-type ESBL is based on dissemination of particular mobile
genetic elements and/or plasmids. However, a more detailed analysis of the genetic environment of blaCTX-M genes indicates that
this is rather due to a series of independent events. The blaCTX-M-15
a
CTX-M types mediating ceftazidime resistance by mutations expanding the substrate spectrum.
Fig. 3. Examples for the genetic environment of blaCTX-M in different plasmids harboured by nosocomial E. coli isolates (Cullik et al., 2010).
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gene which became prevalent in Europe was supposed to be originated from the related, plasmid-encoded blaCTX-M-3 gene which
had spread in Poland recently. The Polish blaCTX-M-3 gene, however, is located in a different distance from ISEcp1 than blaCTX-M-15
in isolates from UK, France, Turkey, Canada, and India (overview
by Livermore et al., 2007). Although blaCTX-M-15 containing E. coli
have firstly been described in India, there is no real evidence for
spreading to UK and France later on. Further more, it remains
unclear why CTX-M-group 9 enzymes (CTX-M-14, CTX-M-16, CTXM-19, CTX-M-27) are predominant in Spain and group 1 enzymes
(CTX-M-1, CTX-M-3, CTX-M-15) in most of the other European
countries (Livermore et al., 2007). For E. coli from nosocomial infections in Germany, an increase of the proportion of CTX-M-15 has
been observed (Table 3). In this study, ESBL types of phenotypically ESBL-positive E. coli from blood cultures, wound infections
and tracheal secretions, isolated in different hospitals throughout
Germany were determined by PCR and sequencing (Pfeifer et al.,
2010a).
A wide dissemination of one particular blaCTX-M-15 containing E. coli strain belonging to serotype O25 ST131 in hospitals
and in the community had been reported for England and Wales
from 2003 to 2005 (Woodford et al., 2004). Interhospital spread
of an E. coli strain expressing blaCTX-M-15 has also been observed
in France (Leflon-Guibout et al., 2004). Plasmid hospitalism was
described for a 90-kb blaCTX-M-15 -containing IncFII plasmid in a
Lebanese hospital (Kanj et al., 2008). In 2006, ESBL-producing E.
coli from a German university hospital were analysed. For 21 of the
22 corresponding isolates, a large potpourri of CTX-M-type ESBL
were detected, representing CTX-M groups 1 (blaCTX-M-1, blaCTX-M-3 ,
blaCTX-M-15 ) and 9 (blaCTX-M-9, blaCTX-M-14 , blaCTX-M-65 ). Additionally, blaCTX-M-1 and blaCTX-M-15 were found to be associated with
plasmids of different incompatibility groups (IncN, IncI1, IncFII).
The analysis of their genetic environment indicated the integration of an IS26/CTX-M element into different plasmids. Because of
their similar genetic neighbourhood (Fig. 3) either hot spots for IS
integration or exchange of a particular larger blaCTX-M containing
module can be supposed (Cullik et al., 2010).
5
Resistance to cephalosporins: AmpC ␤-lactamases
The ampC gene which is contained in the chromosome of nearly
all enterobacterial species besides Klebsiella spp. and Proteus spp. is
regulated by a complex mechanism (Fig. 4). Beta-lactam antibiotics
like cefoxitin induce ampC expression by binding to transpeptidases (penicillin-binding proteins) resulting in a balance shift to
murein degradation (Jacobs et al., 1997). The degradation products (anhydro-muropeptides) are transferred into the cytoplasm
mediated by the AmpD porin (Normark, 1995). Function of these
degradation products in cytoplasm is the activation of the transcriptional regulator AmpR causing increased promoter activity.
The AmpD amidase counteracts this activation by further degradation of muropeptides. Different ampD gene mutations lead to a
functional loss of AmpD and cause constitutive high-level ampC
expression. Another reason for a permanent ampC expression are
specific ampR mutations that reduce the ability of AmpR binding
the UDP-muropeptide repressor (Kuga et al., 2000).
For E. coli, there are 2 options to confer broad-spectrum
cephalosporin resistance mediated by AmpC enzymes:
- high-level expression of the intrinsic E. coli ampC gene by generation of more efficient promoter structures; and
- acquisition of plasmid-borne ampC originating from other enteric
species.
Chromosomal AmpC ˇ-lactamases and cephalosporin resistance
in E. coli
In cephalosporin-susceptible E. coli wild-type strains, the ampC
expression is on a low level because of degenerated promoter
boxes. A mutation at position −42 of the ampC promoter sequence
associated with a mutation at position −18 generates 2 new alternative promoter boxes which result in high-level expression of
chromosomal E. coli ampC and mediating cephalosporin resistance
(Caroff et al., 2000). Furthermore, mutations with in the −10 and
−35 ampC promoter boxes as well as insertions of nucleotides
Fig. 4. Regulation of ampC in Enterobacteriaceae (according to Wiegand, 2003).
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Fig. 5. Examples for mutations in the Escherichia coli ampC promoter sequence generating a new (108/04) or more efficient (67/04; 99/04) promoter in clinical isolates from
nosocomial blood stream infections in a German hospital (Pfeifer and Witte, 2007). * E. coli wild-type ampC promoter sequence; underlined, ampC promoter boxes, single
nucleotide polymorphisms (SNPs) and start codon ATG.
Table 4
Examples for plasmid-mediated AmpC ␤-lactamases in Enterobacteriaceae.
AmpC-type ␤-lactamases
Likely origin
Country and year
Species
References
CMY-1
MIR-1
BIL-1
CMY-2
MOX-1
FOX-1
DHA-1
ACC-1
Aeromonas hydrophila
Enterobacter cloacae
Citrobacter freundii
Citrobacter freundii
Aeromonas hydrophila
Aeromonas caviae
Morganella morganii
Hafnia alvei
South Korea, 1988
USA, 1988
Pakistan, 1989
Greece, 1990
Japan, 1991
Argentina, 1989
Saudi Arabia, 1992
Germany 1997
K. pneumoniae
K. pneumoniae
E. coli
K. pneumoniae
K. pneumoniae
K. pneumoniae
Salmonella enteriditis
K. pneumoniae
Bauernfeind et al. (1989)
Jacoby and Tran (1999)
Payne et al. (1992)
Bauernfeind et al. (1996)
Horii et al. (1993)
Gonzalez et al. (1994)
Gaillot et al. (1997)
Bauernfeind et al. (1999)
between these promoter boxes increase the promoter activity and
entail in high-level ampC expression as described previously (Siu
et al., 2003). Examples of the promoter region of ampC found in
clinical isolates of E. coli are displayed in Fig. 5.
Plasmid-mediated AmpC ˇ-lactamases and cephalosporin
resistance
Constitutive expression of plasmid-located ampC genes mediates resistance to broad-spectrum cephalosporins in species
without own ampC gene (e.g. Klebsiella spp.) or in species with
low-level expression of the intrinsic ampC gene (e.g. E. coli). Starting point was the mobilisation of chromosomal ampC genes from
different enteric bacteria (such as C. freundii and E. cloacae) and horizontal transfer in other species (Philippon et al., 2002). Only a few
mobilization events are likely, e.g. the C. freundii ampC gene seems
to have been mobilized only one time not long ago (Barlow and
Hall, 2002a). The first plasmid-borne ampC gene, namely CMY-1,
was already reported in 1989 (Bauernfeind et al., 1989), followed
by MIR-1 and CMY-2 (Papanicolaou et al., 1990). Until today, a
number of other types like MOX-1, FOX-1, DHA-1, and ACC-1 were
described (Table 4). A closer look at the phylogeny of ampC genes,
based on Bayesian phylogenetic inference, revealed that plasmidborne AmpC ␤-lactamases, e.g. the C. freundii ampC differ from their
ancestors only by a few mutations (overview see also Jacoby, 2009).
However, the amino acid-sequence similarities of AmpC enzymes
from different ancestors are small. At present, the CMY and DHA
␤-lactamases are most frequent AmpC in E. coli and K. pneumoniae,
and a further dissemination and frequency rate is to be expected.
Resistance to carbapenems: class A carbapenemases
Four different groups of class A enzymes exerting carbapenemase activity became recently known:
(i) SME: nearly exclusively associated with S. marcescens with 3
variants described so far (Queenan et al., 2000, 2006);
(ii) IMI (NUC-A): preferentially in E. cloacae (from the United
States, France, and Argentina). Although flanked by tpnA of
Tn5O3, it is not known whether blaIMI is mobile (Rasmussen
et al., 1996);
(iii) GES (named after first detection in K. pneumoniae from
Guiana): sixteen variants are known so far; there are indications for integron location. GES enzymes were mainly found in
P. aeruginosa, but also in K. pneumoniae and E. coli from both
North America and Asia (Poirel et al., 2000a).
(iv) KPC (acronym for K. pneumoniae carbapenemase): ten variants are known so far. KPC-2 and KPC-3 are the most frequent
variants worldwide. The blaKPC genes are located on the novel
tn3-based transposon tn4401 (Naas et al., 2008). KPC-2 was
first described in a carbapenem-resistant K. pneumoniae in
North Carolina in 2001 (Yigit et al., 2001). Furthermore KPC2 was reported in isolates of Salmonella enterica in the USA
(Miriagou et al., 2003), K. oxytoca (Yigit et al., 2003), P. aeruginosa (Villegas et al., 2007), and E. cloacae (Bratu et al., 2005).
KPC-3 was frequently detected in nosocomial K. pneumoniae in
the North East of the USA and in Israel (Bratu et al., 2005; Shiri
et al., 2009). Until today, KPC-producing K. pneumoniae have
also been observed in Europe (Naas et al., 2005) and in Finland
(Österblad et al., 2009), South America (Villegas et al., 2006),
China (Cai et al., 2008), and Germany (Wendt, 2008).
Resistance to carbapenems: class D ␤-lactamases (OXA)
According to the original definition, OXA ␤-lactamases were
named for their ability to hydrolyse oxacillin. Also included are
several oxacillinases with an extended hydrolysis spectrum for
cephalosporins caused by amino acid substitutions (Naas and
Nordmann, 1999; Bush, 1988). Most of these OXA-type ESBL
derive from OXA-10 (e.g. OXA-11, OXA-14, OXA-16, OXA-17)
or in a subcluster from OXA-15 (e.g. OXA-19, OXA-28). OXA2 derivatives are rarer (Walther-Rasmussen and Hoiby, 2006).
The OXA carbapenemases are a number of different class D OXA
enzymes such as OXA-23-like, OXA-24-like, OXA-48, OXA-51-like,
and OXA-58-like (Walther-Rasmussen and Hoiby, 2006). Initially,
OXA-beta-lactamases were reported from P. aeruginosa but until
now, these carbapenemases have been detected in many other
Gram-negative bacteria including Enterobacteriaceae. The natural
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Table 5
Intrinsic and acquired metallo-␤-lactamases (according to Bebrone, 2007).
Subclass
Metallo-enzyme
Bacterial species
Year of first description
B1, intrinsic
BcII
CcrA
BlaB
IND-1
EBR-1
SFB-1
SLB-1
Bacillus cereus
Bacillus fragilis
Elizabethkingia meningoseptica
Chryseobacterium indologenes
Empedobacter brevis
Shewanella frigdimarina
Shewanella livingstonens
1966
1990
1998
1999
2002
2005
2005
B1, acquired
IMP-1
VIM-1
IMP-2
VIM-2
SPM-1
GIM-1
SIM-1
P. aeruginosa, S. marcescens
A. baumannii, P. aeruginosa
S. marcescens, A. baumannii
P. aeruginosa, A. baumannii
P. aeruginosa
P. aeruginosa
A. baumannii
1994
1999
2000
2000
2002
2004
2005
B2, intrinsic
CphA
ImiS
Sfh-1
Aeromonas hydrophila
Aeromonas veronii
Serratia fonticola
1991
1996
2003
B3, intrinsic
GOB-1
FEZ-1
THIN-3
Mbl1b
CAU-1
BJP-1
Elizabethkingia meningoseptica
Legionella gormanii
Janthinobacterium lividum
Caulobacter crescentus
Caulobacter vibrioides
Bradyrhizobium japonicum
2000
2000
2001
2001
2002
2006
reservoir of blaOXA genes is most probably in environmental bacteria e.g. Ralstonia spp., Burkholderia spp. as well as in deep cold see
microflora such as Shewanella spp. (Heritier et al., 2004). The big
family of OXA carbapenemases is very diverse and blaOXA genes
are located on both chromosomes and plasmids. A study based
on Bayesian phylogeny of blaOXA genes revealed that this diversity
results mainly from ancient events as well as the mobilization from
chromosomes to plasmids occurred millions of years ago (Barlow
and Hall, 2002b).
Chromosomal-encoded blaOXA genes play a particular role in
antibiotic resistance of Acinetobacter baumannii. OXA-51-like ␤lactamases in this species are strongly associated with the 3 major
epidemic lineages (“European” clones I, II, and III as defined by AFLP;
Evans et al., 2008). The blaOXA-51-like genes are of special interest
because they seem to be ubiquitous in A. baumannii. Insertion of
ISAba1 upstream blaOXA-51-like provides a strong promoter resulting
in enhanced gene expression and carbapenem resistance (Merkier
and Centron, 2006; Turton et al., 2006).
The wide geographical dissemination of OXA carbapenemases is
obviously associated with travelling of patients. In Germany, 2 outbreaks of infections with multiresistant A. baumannii were recorded
in 2007, in total 16 patients and 9 patients, respectively; unfortunately, associated with a number of fatal outcomes. Plasmid-borne
OXA-58 was identified in the first and OXA-23 in the second outbreak. For both events, an acquisition of the epidemic strain by the
index patient in a hospital abroad was likely (Pfeifer et al., 2010b).
Resistance to carbapenems: class B metallo-␤-lactamases
(MBL)
MBL belong to a superfamily of enzymes with wide catalytic diversity [(oxydoreductases, glyoxylases, phosphoryl
cholinesterase (for review see Bebrone, 2007)]. These enzymes
are basically able to hydrolyse all ␤-lactam antibiotics except
monobactams. Based on DNA sequence alignments of the genes,
MBL are classified into 3 subclasses: B1, B2, and B3 (Garau et
al., 2004). Although there is a low degree of similarity between
the determinants of the subclasses, this grouping is supported
by crystallographic analysis of the corresponding enzymes. The
ability of MBL production has not only been detected in Gram-
negative bacterial pathogens, but also in a surprising number of
environmental bacteria. An overview is shown in Table 5.
Especially subclass B1 MBL genes (intrinsic or acquired) were
found in many bacterial species. Recently the new MBL enzyme
NDM-1 was identified in K. pneumoniae (Dongeun et al., 2009). In
contrast, subclass 2 enzymes were mostly identified in different
Aeromonas species (Walsh et al., 1996). Subclass B3 enzymes are
intrinsic in a number of different environmental species from which
some of them can come out as nosocomial pathogen in immunocompromized patients (e.g. S. maltophilia; Walsh et al., 1994, 2005).
Dissemination of acquired subclass B1 MBL
The most frequent MBL acquired by Gram-negative bacterial
pathogens are of IMP and VIM type. These enzymes were originally described in P. aeruginosa and A. baumannii, but today
they are also spread in Enterobacteriaceae (Poirel et al., 2000b;
Tortola et al., 2005). For VIM-type enzymes, 12 allelic variants
are known so far (Walsh et al., 2005). The emergence of different
VIM and IMP subtypes in different geographical areas suggests that
the corresponding genes have been captured independently from
(unknown) natural reservoirs. This view is supported by reports on
more rarely acquired MBL: SPM-1 in South America (Toleman et al.,
2002), GIM-1 in Germany (Castanheira et al., 2004), and SIM-1 in
Korea (Lee et al., 2005). The genetic determinants for these acquired
MBL are in most cases incorporated in type 1 or type 3 integrons
located on large plasmids or the chromosome. For blaSPM-1 , an association with the ISCR44 element has been described. These insertion
elements are able to mobilize long stretches of adjacent DNA, most
probably by rolling circle replications. ISCR elements have also been
described for P. aeruginosa with blaIMP-1 and blaVIM-1 (Toleman et
al., 2006).
Carbapenemase-producing, multidrug-resistant K.
pneumoniae, the forerunner of an end of the antibiotic era?
In K. pneumoniae, there is a variety of mechanisms to elude the
effect of carbapenems: (a) AmpC production plus porin loss; (b)
production of a “classical” ESBL plus porin loss; (c) production of
carbapenemases such as KPC or OXA; as well as (d) production of
Please cite this article in press as: Pfeifer, Y., et al., Resistance to cephalosporins and carbapenems in Gram-negative bacterial pathogens. Int. J.
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acquired MBL (Jacoby et al., 2004). Multidrug-resistant K. pneumoniae have been described from many parts of the world such as
Greece, the Near East, the United States (Deshpande et al., 2006).
This development is reflected by 3 examples from Germany (Pfeifer
and Witte, 2008; Wendt, 2008):
(i) a cluster of infections (n = 4) in 2 German hospitals associated
with K. pneumoniae producing a combination of 3 enzymes
(VIM-1, CMY-4, CTX-M-9) in each strain and conferring resistance to all available antibiotics but colistin,
(ii) a cluster of infections (n = 5) in 2 German hospitals with
multidrug-resistant K. oxytoca containing blaVIM-1 , qnrB2, and
deletions in porin genes ompK35/36 resulting in a translational
stop,
(iii) a cluster of infections with KPC-2-producing K. pneumoniae
and E. coli in Germany conferring resistance to all antibiotics
except colistin.
Infections with carbapenem-resistant Enterobacteriaceae are
still rare in many European countries (see also Fig. 2). However,
dissemination of multidrug-resistant strains or the conjugative
transfer of multidrug resistance-mediating plasmids are of major
concern since the therapeutic options are severely restricted
attended by an increasing risk of fatal outcomes. This displays the
urgent need of resistance surveillance and molecular analysis for
Gram-negative nosocomial pathogens.
References
Ambler, R.P., 1980. The structure of beta-lactamases. Philos. Trans. R. Soc. Lond. B
Biol. Sci. 289, 321–331.
Barlow, M., Hall, B.G., 2002a. Origin and evolution of the AmpC beta-lactamases of
Citrobacter freundii. Antimicrob. Agents Chemother. 46, 1190–1198.
Barlow, M., Hall, B.G., 2002b. Phylogenetic analysis shows that the OXA betalactamase genes have been on plasmids for millions of years. J. Mol. Evol. 55,
314–321.
Barlow, M., Reik, R.A., Jacobs, S.D., Medina, M., Meyer, M.P., McGowan Jr., J.E., Tenover, F.C., 2008. High rate of mobilization for blaCTX-Ms. Emerg. Infect. Dis. 14,
423–428.
Bauernfeind, A., Chong, Y., Schweighart, S., 1989. Extended broad spectrum
beta-lactamase in Klebsiella pneumoniae including resistance to cephamycins.
Infection 17, 316–321.
Bauernfeind, A., Stemplinger, I., Jungwirth, R., Giamarellou, H., 1996. Characterization of the plasmidic beta-lactamase CMY-2, which is responsible for
cephamycin resistance. Antimicrob. Agents Chemother. 40, 221–224.
Bauernfeind, A., Schneider, I., Jungwirth, R., Sahly, H., Ullmann, U., 1999. A novel
type of AmpC beta-lactamase, ACC-1, produced by a Klebsiella pneumoniae strain
causing nosocomial pneumonia. Antimicrob. Agents Chemother. 43, 1924–1931.
Bebrone, C., 2007. Metallo-beta-lactamases (classification, activity, genetic organization, structure, zinc coordination) and their superfamily. Biochem. Pharmacol.
74, 1686–1701.
Bonnet, R., 2004. Growing group of extended-spectrum beta-lactamases: the CTX-M
enzymes. Antimicrob. Agents Chemother. 48, 1–14.
Branger, C., Zamfir, O., Geoffroy, S., Laurans, G., Arlet, G., Thien, H.V., Gouriou,
S., Picard, B., Denamur, E., 2005. Genetic background of Escherichia coli and
extended-spectrum beta-lactamase type. Emerg. Infect. Dis. 11, 54–61.
Bratu, S., Landman, D., Alam, M., Tolentino, E., Quale, J., 2005. Detection of KPC
carbapenem-hydrolyzing enzymes in Enterobacter spp. from Brooklyn, New
York. Antimicrob. Agents Chemother. 49, 776–778.
Bush, K., 1988. Recent developments in beta-lactamase research and their implications for the future. Rev. Infect. Dis. 10, 681–690.
Bush, K., 1998. Metallo-beta-lactamases: a class apart. Clin. Infect. Dis. 27 (Suppl. 1),
S48–S53.
Bush, K., Jacoby, G.A., Medeiros, A.A., 1995. A functional classification scheme
for beta-lactamases and its correlation with molecular structure. Antimicrob.
Agents Chemother. 39, 1211–1233.
Cai, J.C., Zhou, H.W., Zhang, R., Chen, G.X., 2008. Emergence of Serratia marcescens,
Klebsiella pneumoniae, and Escherichia coli isolates possessing the plasmidmediated carbapenem-hydrolyzing beta-lactamase KPC-2 in intensive care
units of a Chinese hospital. Antimicrob. Agents Chemother. 52, 2014–2018.
Caroff, N., Espaze, E., Gautreau, D., Richet, H., Reynaud, A., 2000. Analysis of the effects
of −42 and −32 ampC promoter mutations in clinical isolates of Escherichia coli
hyperproducing ampC. J. Antimicrob. Chemother. 45, 783–788.
Cartelle, M., del Mar, T.M., Molina, F., Moure, R., Villanueva, R., Bou, G., 2004. Highlevel resistance to ceftazidime conferred by a novel enzyme, CTX-M-32, derived
from CTX-M-1 through a single Asp240-Gly substitution. Antimicrob. Agents
Chemother. 48, 2308–2313.
Castanheira, M., Toleman, M.A., Jones, R.N., Schmidt, F.J., Walsh, T.R., 2004. Molecular
characterization of a beta-lactamase gene, blaGIM-1, encoding a new subclass
of metallo-beta-lactamase. Antimicrob. Agents Chemother. 48, 4654–4661.
Cullik, A., Pfeifer, Y., Prager, R., von Baum, H., Witte, W., 2010. A novel IS26 structure
is surrounding blaCTX-M genes in different plasmids of German clinical isolates
of Escherichia coli. J. Med. Microbiol. 59, 580–587.
Deshpande, L.M., Jones, R.N., Fritsche, T.R., Sader, H.S., 2006. Occurrence and characterization of carbapenemase-producing Enterobacteriaceae: report from the
SENTRY Antimicrobial Surveillance Program (2000–2004). Microb. Drug Resist.
12, 223–230.
Dongeun, Y., Toleman, M.A., Giske, C.G., Cho, H.S., Sundman, K., Lee, K., Walsh, T.R.,
2009. Characterization of a new metallo-beta-lactamase gene, blaNDM-1, and a
novel erythromycin esterase gene carried on a unique genetic structure in Klebsiella pneumoniae sequence type 14 from India. Antimicrob. Agents Chemother.
53, 5046–5054.
Eckert, C., Gautier, V., Saladin-Allard, M., Hidri, N., Verdet, C., Ould-Hocine, Z.,
Barnaud, G., Delisle, F., Rossier, A., Lambert, T., Philippon, A., Arlet, G., 2004.
Dissemination of CTX-M-type beta-lactamases among clinical isolates of Enterobacteriaceae in Paris, France. Antimicrob. Agents Chemother. 48, 1249–
1255.
Evans, B.A., Hamouda, A., Towner, K.J., Amyes, S.G., 2008. OXA-51-like betalactamases and their association with particular epidemic lineages of
Acinetobacter baumannii. Clin. Microbiol. Infect. 14, 268–275.
Gaillot, O., Clement, C., Simonet, M., Philippon, A., 1997. Novel transferable betalactam resistance with cephalosporinase characteristics in Salmonella enteritidis.
J. Antimicrob. Chemother. 39, 85–87.
Garau, G., Garcia-Saez, I., Bebrone, C., Anne, C., Mercuri, P., Galleni, M., Frere, J.M.,
Dideberg, O., 2004. Update of the standard numbering scheme for class B betalactamases. Antimicrob. Agents Chemother. 48, 2347–2349.
Gonzalez, L.M., Perez-Diaz, J.C., Ayala, J., Casellas, J.M., Martinez-Beltran, J., Bush,
K., Baquero, F., 1994. Gene sequence and biochemical characterization of
FOX-1 from Klebsiella pneumoniae, a new AmpC-type plasmid-mediated betalactamase with two molecular variants. Antimicrob. Agents Chemother. 38,
2150–2157.
Heritier, C., Poirel, L., Nordmann, P., 2004. Genetic and biochemical characterization of a chromosome-encoded carbapenem-hydrolyzing ambler class D
beta-lactamase from Shewanella algae. Antimicrob. Agents Chemother. 48,
1670–1675.
Horii, T., Arakawa, Y., Ohta, M., Ichiyama, S., Wacharotayankun, R., Kato, N., 1993.
Plasmid-mediated AmpC-type beta-lactamase isolated from Klebsiella pneumoniae confers resistance to broad-spectrum beta-lactams, including moxalactam.
Antimicrob. Agents Chemother. 37, 984–990.
Jacobs, C., Frere, J.M., Normark, S., 1997. Cytosolic intermediates for cell wall
biosynthesis and degradation control inducible beta-lactam resistance in gramnegative bacteria. Cell 88, 823–832.
Jacoby, G.A., 2009. AmpC beta-lactamases. Clin. Microbiol. Rev. 22, 161–182.
Jacoby, G.A., Tran, J., 1999. Sequence of the MIR-1 beta-lactamase gene. Antimicrob.
Agents Chemother. 43, 1759–1760.
Jacoby, G.A., Mills, D.M., Chow, N., 2004. Role of beta-lactamases and porins in resistance to ertapenem and other beta-lactams in Klebsiella pneumoniae. Antimicrob.
Agents Chemother. 48, 3203–3206.
Jarlier, V., Nicolas, M.H., Fournier, G., Philippon, A., 1988. Extended broad-spectrum
beta-lactamases conferring transferable resistance to newer beta-lactam agents
in Enterobacteriaceae: hospital prevalence and susceptibility patterns. Rev.
Infect. Dis. 10, 867–878.
Jaurin, B., Grundström, T., 1981. ampC cephalosporinase of Escherichia coli K-12 has
a different evolutionary origin from that of beta-lactamases of the penicillinase
type. Proc. Natl. Acad. Sci. U.S.A. 78, 4897–4901.
Jeong, S.H., Bae, I.K., Lee, J.H., Sohn, S.G., Kang, G.H., Jeon, G.J., Kim, Y.H., Jeong,
B.C., Lee, S.H., 2004. Molecular characterization of extended-spectrum betalactamases produced by clinical isolates of Klebsiella pneumoniae and Escherichia
coli from a Korean nationwide survey. J. Clin. Microbiol. 42, 2902–2906.
Kanj, S.S., Corkill, J.E., Kanafani, Z.A., Araj, G.F., Hart, C.A., Jaafar, R., Matar, G.M., 2008.
Molecular characterisation of extended-spectrum beta-lactamase-producing
Escherichia coli and Klebsiella spp. isolates at a tertiary-care centre in Lebanon.
Clin. Microbiol. Infect. 14, 501–504.
Kuga, A., Okamoto, R., Inoue, M., 2000. ampR gene mutations that greatly increase
class C beta-lactamase activity in Enterobacter cloacae. Antimicrob. Agents
Chemother. 44, 561–567.
Lee, K., Yum, J.H., Yong, D., Lee, H.M., Kim, H.D., Docquier, J.D., Rossolini, G.M., Chong,
Y., 2005. Novel acquired metallo-beta-lactamase gene, bla(SIM-1), in a class 1
integron from Acinetobacter baumannii clinical isolates from Korea. Antimicrob.
Agents Chemother. 49, 4485–4491.
Leflon-Guibout, V., Jurand, C., Bonacorsi, S., Espinasse, F., Guelfi, M.C., Duportail, F.,
Heym, B., Bingen, E., Nicolas-Chanoine, M.H., 2004. Emergence and spread of
three clonally related virulent isolates of CTX-M-15-producing Escherichia coli
with variable resistance to aminoglycosides and tetracycline in a French geriatric
hospital. Antimicrob. Agents Chemother. 48, 3736–3742.
Livermore, D.M., Canton, R., Gniadkowski, M., Nordmann, P., Rossolini, G.M., Arlet,
G., Ayala, J., Coque, T.M., Kern-Zdanowicz, I., Luzzaro, F., Poirel, L., Woodford, N.,
2007. CTX-M: changing the face of ESBLs in Europe. J. Antimicrob. Chemother.
59, 165–174.
Machado, E., Canton, R., Baquero, F., Galan, J.C., Rollan, A., Peixe, L., Coque, T.M., 2005.
Integron content of extended-spectrum-beta-lactamase-producing Escherichia
coli strains over 12 years in a single hospital in Madrid, Spain. Antimicrob. Agents
Chemother. 49, 1823–1829.
Please cite this article in press as: Pfeifer, Y., et al., Resistance to cephalosporins and carbapenems in Gram-negative bacterial pathogens. Int. J.
Med. Microbiol. (2010), doi:10.1016/j.ijmm.2010.04.005
G Model
IJMM-50480;
No. of Pages 9
ARTICLE IN PRESS
Y. Pfeifer et al. / International Journal of Medical Microbiology xxx (2010) xxx–xxx
Martinez-Martinez, L., Eliecer, C.M., Manuel Rodriguez-Martinez, J., Calvo, J., Pascual,
A., 2008. Plasmid-mediated quinolone resistance. Expert Rev. Anti Infect. Ther.
6, 685–711.
Merkier, A.K., Centron, D., 2006. bla(OXA-51)-type beta-lactamase genes are ubiquitous and vary within a strain in Acinetobacter baumannii. Int. J. Antimicrob.
Agents 28, 110–113.
Pfeifer, Y., Cullik, A., Eckmanns, T., Noll, I., Witte, W., 2010a. ESBL in nosocomial
Enterobacteriaceae from Germany – a one-year study. Abstr. 62th DGHM and
VAAM Conf. Biospektrum. Abstr. KMP13.
Pfeifer, Y., Cho, S.H., Higgins, P.G., Fahr, A.M., Wichelhaus, T.A., Hunfeld, K.P., Martin, M. Witte, W., 2010b. Molecular characterisation and outbreak analysis of
multidrug- resistant Acinetobacter baumannii from German hospitals. Abstr.
20th European Congress of Clinical Microbiology and Infectious Diseases. Abstr.
P797.
Miriagou, V., Tzouvelekis, L.S., Rossiter, S., Tzelepi, E., Angulo, F.J., Whichard, J.M.,
2003. Imipenem resistance in a Salmonella clinical strain due to plasmidmediated class A carbapenemase KPC-2. Antimicrob. Agents Chemother. 47,
1297–1300.
Naas, T., Nordmann, P., 1999. OXA-type beta-lactamases. Curr. Pharm. Des. 5,
865–879.
Naas, T., Nordmann, P., Vedel, G., Poyart, C., 2005. Plasmid-mediated carbapenemhydrolyzing beta-lactamase KPC in a Klebsiella pneumoniae isolate from France.
Antimicrob. Agents Chemother. 49, 4423–4424.
Naas, T., Cuzon, G., Villegas, M.V., Lartigue, M.F., Quinn, J.P., Nordmann, P., 2008.
Genetic structures at the origin of acquisition of the beta-lactamase blaKPC gene.
Antimicrob. Agents Chemother. 52, 1257–1263.
Navarro, F., Mesa, R.J., Miro, E., Gomez, L., Mirelis, B., Coll, P., 2007. Evidence for
convergent evolution of CTX-M-14 ESBL in Escherichia coli and its prevalence.
FEMS Microbiol. Lett. 273, 120–123.
Normark, S., 1995. beta-lactamase induction in gram-negative bacteria is intimately
linked to peptidoglycan recycling. Microb. Drug Resist. 1, 111–114.
Novais, A., Canton, R., Coque, T.M., Moya, A., Baquero, F., Galan, J.C., 2008. Mutational
events in cefotaximase extended-spectrum beta-lactamases of the CTX-M-1
cluster involved in ceftazidime resistance. Antimicrob. Agents Chemother. 52,
2377–2382.
Österblad, M., Kirveskari, J., Koskela, S., Tissari, P., Vuorenoja, K., Hakanen, A.J., Vaara,
M., Jalava, J., 2009. First isolations of KPC-2-carrying ST258 Klebsiella pneumoniae strains in Finland, June and August 2009. Euro Surveill.14, pii: 19349.
Ouellette, M., Bissonnette, L., Roy, P.H., 1987. Precise insertion of antibiotic resistance
determinants into Tn21-like transposons: nucleotide sequence of the OXA-1
beta-lactamase gene. Proc. Natl. Acad. Sci. U.S.A. 84, 7378–7382.
Page, M.G., 2008. Extended-spectrum beta-lactamases: structure and kinetic mechanism. Clin. Microbiol. Infect. 14 (Suppl. 1), 63–74.
Papanicolaou, G.A., Medeiros, A.A., Jacoby, G.A., 1990. Novel plasmid-mediated
beta-lactamase (MIR-1) conferring resistance to oxyimino- and alpha-methoxy
beta-lactams in clinical isolates of Klebsiella pneumoniae. Antimicrob. Agents
Chemother. 34, 2200–2209.
Paterson, D.L., Bonomo, R.A., 2005. Extended-spectrum beta-lactamases: a clinical
update. Clin. Microbiol. Rev. 18, 657–686.
Payne, D.J., Woodford, N., Amyes, S.G., 1992. Characterization of the plasmid mediated beta-lactamase BIL-1. J. Antimicrob. Chemother. 30, 119–127.
Pfeifer, Y., Witte, W., 2007. ESBL und AmpC: Beta-Lactamasen als eine Hauptursache
der Cephalosporin-Resistenz bei Enterobakterien. Epidemiol. Bull. 28, 247–250.
Pfeifer, Y., Witte, W., 2008. Resistenzentwicklung erreicht die Grenzen der therapeutischen Möglichkeiten: Multiresistente Klebsiella pneumoniae mit ESBL,
AmpC- und Metallo-Beta-Lactamasen. Epidemiol. Bull. 14, 110–113.
Philippon, A., Arlet, G., Jacoby, G.A., 2002. Plasmid-determined AmpC-type betalactamases. Antimicrob. Agents Chemother. 46, 1–11.
Pitout, J.D., Nordmann, P., Laupland, K.B., Poirel, L., 2005. Emergence of Enterobacteriaceae producing extended-spectrum beta-lactamases (ESBLs) in the community.
J. Antimicrob. Chemother. 56, 52–59.
Poirel, L., Naas, T., Nicolas, D., Collet, L., Bellais, S., Cavallo, J.D., Nordmann, P., 2000a.
Characterization of VIM-2, a carbapenem-hydrolyzing metallo-beta-lactamase
and its plasmid- and integron-borne gene from a Pseudomonas aeruginosa clinical isolate in France. Antimicrob. Agents Chemother. 44, 891–897.
Poirel, L., Le Thomas, I., Naas, T., Karim, A., Nordmann, P., 2000b. Biochemical
sequence analyses of GES-1, a novel class A extended-spectrum beta-lactamase,
and the class 1 integron In52 from Klebsiella pneumoniae. Antimicrob. Agents
Chemother. 44, 622–632.
Poirel, L., Gniadkowski, M., Nordmann, P., 2002. Biochemical analysis of the
ceftazidime-hydrolysing extended-spectrum beta-lactamase CTX-M-15 and of
its structurally related beta-lactamase CTX-M-3. J. Antimicrob. Chemother. 50,
1031–1034.
Poirel, L., Lartigue, M.F., Decousser, J.W., Nordmann, P., 2005. ISEcp1B-mediated
transposition of blaCTX-M in Escherichia coli. Antimicrob. Agents Chemother.
49, 447–450.
Queenan, A.M., Torres-Viera, C., Gold, H.S., Carmeli, Y., Eliopoulos, G.M., Moellering Jr., R.C., Quinn, J.P., Hindler, J., Medeiros, A.A., Bush, K., 2000. SME-type
carbapenem-hydrolyzing class A beta-lactamases from geographically diverse
Serratia marcescens strains. Antimicrob. Agents Chemother. 44, 3035–3039.
9
Queenan, A.M., Shang, W., Schreckenberger, P., Lolans, K., Bush, K., Quinn, J., 2006.
SME-3, a novel member of the Serratia marcescens SME family of carbapenemhydrolyzing beta-lactamases. Antimicrob. Agents Chemother. 50, 3485–3487.
Raquet, X., Vanhove, M., Lamotte-Brasseur, J., Goussard, S., Courvalin, P., Frere, J.M.,
1995. Stability of TEM beta-lactamase mutants hydrolyzing third generation
cephalosporins. Proteins 23, 63–72.
Rasmussen, B.A., Bush, K., Keeney, D., Yang, Y., Hare, R., O’Gara, C., Medeiros,
A.A., 1996. Characterization of IMI-1 beta-lactamase, a class A carbapenemhydrolyzing enzyme from Enterobacter cloacae. Antimicrob. Agents Chemother.
40, 2080–2086.
Rodriguez-Bano, J., Navarro, M.D., Romero, L., Martinez-Martinez, L., Muniain, M.A.,
Perea, E.J., Perez-Cano, R., Pascual, A., 2004. Epidemiology and clinical features of
infections caused by extended-spectrum beta-lactamase-producing Escherichia
coli in nonhospitalized patients. J. Clin. Microbiol. 42, 1089–1094.
Sanders Jr., W.E., Sanders, C.C., 1988. Inducible beta-lactamases: clinical and epidemiologic implications for use of newer cephalosporins. Rev. Infect. Dis. 10,
830–838.
Shiri, N.V., Leavitt, A., Schwaber, M.J., Rasheed, J.K., Srinivasan, A., Patel, J.B., Carmeli,
Y., 2009. First report on a hyperepidemic clone of KPC-3-producing Klebsiella
pneumoniae in Israel genetically related to a strain causing outbreaks in the
United States. Antimicrob. Agents Chemother. 53, 818–820.
Sirot, J., Chanal, C., Petit, A., Sirot, D., Labia, R., Gerbaud, G., 1988. Klebsiella
pneumoniae and other Enterobacteriaceae producing novel plasmid-mediated
beta-lactamases markedly active against third-generation cephalosporins: epidemiologic studies. Rev. Infect. Dis. 10, 850–859.
Siu, L.K., Lu, P.L., Chen, J.Y., Lin, F.M., Chang, S.C., 2003. High-level expression of
ampC beta-lactamase due to insertion of nucleotides between −10 and −35
promoter sequences in Escherichia coli clinical isolates: cases not responsive to
extended-spectrum-cephalosporin treatment. Antimicrob. Agents Chemother.
47, 2138–2144.
Stepanova, M.N., Pimkin, M., Nikulin, A.A., Kozyreva, V.K., Agapova, E.D., Edelstein,
M.V., 2008. Convergent in vivo and in vitro selection of ceftazidime resistance mutations at position 167 of CTX-M-3 beta-lactamase in hypermutable
Escherichia coli strains. Antimicrob. Agents Chemother. 52, 1297–1301.
Toleman, M.A., Simm, A.M., Murphy, T.A., Gales, A.C., Biedenbach, D.J., Jones, R.N.,
Walsh, T.R., 2002. Molecular characterization of SPM-1, a novel metallo-betalactamase isolated in Latin America: report from the SENTRY antimicrobial
surveillance programme. J. Antimicrob. Chemother. 50, 673–679.
Toleman, M.A., Bennett, P.M., Walsh, T.R., 2006. ISCR elements: novel gene-capturing
systems of the 21st century? Microbiol. Mol. Biol. Rev. 70, 296–316.
Tortola, M.T., Lavilla, S., Miro, E., Gonzalez, J.J., Larrosa, N., Sabate, M., Navarro, F.,
Prats, G., 2005. First detection of a carbapenem-hydrolyzing metalloenzyme
in two Enterobacteriaceae isolates in Spain. Antimicrob. Agents Chemother. 49,
3492–3494.
Turton, J.F., Ward, M.E., Woodford, N., Kaufmann, M.E., Pike, R., Livermore, D.M.,
Pitt, T.L., 2006. The role of ISAba1 in expression of OXA carbapenemase genes in
Acinetobacter baumannii. FEMS Microbiol. Lett. 258, 72–77.
Villegas, M.V., Lolans, K., Correa, A., Kattan, J.N., Lopez, J.A., Quinn, J.P., 2007.
First identification of Pseudomonas aeruginosa isolates producing a KPC-type
carbapenem-hydrolyzing beta-lactamase. Antimicrob. Agents Chemother. 51,
1553–1555.
Walsh, T.R., Hall, L., Assinder, S.J., Nichols, W.W., Cartwright, S.J., MacGowan, A.P.,
Bennett, P.M., 1994. Sequence analysis of the L1 metallo-beta-lactamase from
Xanthomonas maltophilia. Biochim. Biophys. Acta 1218, 199–201.
Walsh, T.R., Gamblin, S., Emery, D.C., MacGowan, A.P., Bennett, P.M., 1996. Enzyme
kinetics and biochemical analysis of ImiS, the metallo-beta-lactamase from
Aeromonas sobria 163a. J. Antimicrob. Chemother. 37, 423–431.
Walsh, T.R., Toleman, M.A., Poirel, L., Nordmann, P., 2005. Metallo-beta-lactamases:
the quiet before the storm? Clin. Microbiol. Rev. 18, 306–325.
Walther-Rasmussen, J., Hoiby, N., 2006. OXA-type carbapenemases. J. Antimicrob.
Chemother. 57, 373–383.
Wendt, C., 2008. Klebsiella-pneumoniae-Carbapenemase in Deutschland diese
Woche 22/2008 nachgewiesen. Epidemiol. Bull. 22, 173–174.
Wiegand, I., 2003. Molekulare und biochemische Grundlagen der Beta-LactamResistenz durch Beta-Lactamasen. Chemother. J. 12, 151–167.
Woodford, N., Ward, M.E., Kaufmann, M.E., Turton, J., Fagan, E.J., James, D., Johnson,
A.P., Pike, R., Warner, M., Cheasty, T., Pearson, A., Harry, S., Leach, J.B., Loughrey,
A., Lowes, J.A., Warren, R.E., Livermore, D.M., 2004. Community and hospital
spread of Escherichia coli producing CTX-M extended-spectrum beta-lactamases
in the UK. J. Antimicrob. Chemother. 54, 735–743.
Yigit, H., Queenan, A.M., Anderson, G.J., Domenech-Sanchez, A., Biddle, J.W., Steward, C.D., Alberti, S., Bush, K., Tenover, F.C., 2001. Novel carbapenem-hydrolyzing
beta-lactamase, KPC-1, from a carbapenem-resistant strain of Klebsiella pneumoniae. Antimicrob. Agents Chemother. 45, 1151–1161.
Yigit, H., Queenan, A.M., Rasheed, J.K., Biddle, J.W., Domenech-Sanchez, A., Alberti,
S., Bush, K., Tenover, F.C., 2003. Carbapenem-resistant strain of Klebsiella oxytoca
harboring carbapenem-hydrolyzing beta-lactamase KPC-2. Antimicrob. Agents
Chemother. 47, 3881–3889.
Please cite this article in press as: Pfeifer, Y., et al., Resistance to cephalosporins and carbapenems in Gram-negative bacterial pathogens. Int. J.
Med. Microbiol. (2010), doi:10.1016/j.ijmm.2010.04.005