REVIEW

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Carbapenemase-producing
Gram-negative bacteria: current
epidemics, antimicrobial susceptibility
and treatment options

Shio-Shin Jean1, Wen-Sen Lee2, Carlos Lam1, Chin-Wang Hsu3, Ray-Jade Chen3
& Po-Ren Hsueh*,4

ABSTRACT Carbapenemases, with versatile hydrolytic capacity against β-lactams, are

now an important cause of resistance of Gram-negative bacteria. The genes encoding for the
acquired carbapenemases are associated with a high potential for dissemination. In addition,
infections due to Gram-negative bacteria with acquired carbapenemase production would
lead to high clinical mortality rates. Of the acquired carbapenemases, Klebsiella pneumoniae
carbapenemase (Ambler class A), Verona integron-encoded metallo-β-lactamase (Ambler
class B), New Delhi metallo-β-lactamase (Ambler class B) and many OXA enzymes (OXA-
23-like, OXA-24-like, OXA-48-like, OXA-58-like, class D) are considered to be responsible
for the worldwide resistance epidemics. As compared with monotherapy with colistin or
tigecycline, combination therapy has been shown to effectively lower case-fatality rates.
However, development of new antibiotics is crucial in the present pandrug-resistant era.

Carbapenemases are β-lactamases with versatile hydrolytic capacity against β-lactam agents (includ- KEYWORDS 
ing carbapenem agents) [1] . The β-lactamases are classified according to their functional groups • carbapenemase
(Bush-Jacoby-Medeiros, groups 1–4, with many subgroups) or molecular schemes (Ambler, class • combination therapy
A–D). Currently, carbapenemases mainly fall under functional group 2d, 2f or 3. According to • dissemination
the Ambler classification system, they are categorized as class A, B or D [2] . Of them, molecular • Gram-negative bacteria
class-B β-lactamases are metallic ion-dependent enzymes, such as metallo-β-lactamases [MβL], • resistance
which possess divalent cations (usually zinc) in the active site that are essential for hydrolysis of
the β-lactam ring, whereas class A and D β-lactamases have serine at their active sites. Most of the
genes encoding for these carbapenemases are associated with high potential for intra- and inter-
hospital dissemination [1,3–14] . The prevalence of a variety of carbapenemases in Gram-negative
bacteria (GNB) has increased markedly during the previous 10 years [1,15] . These carbapenemases
compromise the efficacies of all carbapenem-class drugs, which are often the last resort against
serious infections in hospitals, long-term acute care hospitals and long-term care facilities [16] . In
this review, we summarize the genetic background, epidemiology and nonsusceptibility profiles of
carbapenemase-producing GNB (Enterobacteriaceae and Acinetobacter spp.), and the clinical out-
come of patients with infections caused by carbapenemase-producing GNB after various therapies.
1
Department of Emergency Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
2
Division of infectious Diseases, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
3
Department of Emergency & Critical Medicine, Taipei Medical University, Wan Fang Hospital, Taipei, Taiwan
4
Departments of Laboratory Medicine & Internal Medicine, National Taiwan University Hospital, National Taiwan University College of
Medicine, Taipei, Taiwan
*Author for correspondence: hsporen@ntu.edu.tw part of

10.2217/FMB.14.135  © 2015 Future Medicine Ltd Future Microbiol. (2015) 10(3), 407–425 ISSN 1746-0913 407
Review  Jean, Lee, Lam, Hsu, Chen & Hsueh
Molecular class A carbapenemases
The class A group of serine carbapenemases
include not metalloenzyme carbapenemase
(NMC)/imipenem-hydrolyzing β-lactamase
(IMI), Serratia marcescens enzyme (SME),
Klebsiella pneumoniae carbapenemase (KPC)
and Guiana extended spectrum (GES) enzymes.
●●KPC
The blaKPC genes reside on transferable plasmids,
thereby posing a formidable threat to infection
control and survival of critically ill patients [3,17–
19] . The bla KPC-2 gene has been found to share
high degrees of amino-acid sequence identity
with blaKPC-3 [20] . Analysis of genetic sequences
flanking blaKPC genes on plasmids of K. pneu-
moniae has revealed that transposase (tnpA),
resolvase (tnpR) and two unrelated insertion
sequences (IS; ISKpn6, ISKpn7; or a substitu-
tion of ISKpn8 for ISKpn7) are all invariable
components on mobile transposons (a 10 kilo-
base, Tn3-based transposon, Tn4401) [3,21] . The
facts that transposons are only located on a few
different Inc groups of plasmid during the repli-
cative process, and that there is limited diversity
of transposon structure, corresponded well with
few epidemic clones of KPC producers with dis-
tinct sequence types (STs; predominantly ST258
and ST11) being identified [1,21,22] . It is notewor-
thy that ST11 and ST258 are phylogenetically
related [19] . The results of recent in vitro conjuga-
tion experiments showed that blaKPC-2 could be
transferred with the assistance of flanking IS26
(in the form of composite transposon) and the
transfer operon (locus tra-trb) in Escherichia coli
but not in K. pneumoniae [23] . The cross-species
transmission of the blaKPC-2 gene is, therefore, a
worrisome reality. However, the other molecular
investigation has also proven that the horizontal
transfers of plasmid (IncFIA type) have also con-
tributed to disseminations of the bla KPC genes
between different Enterobacteriaceae spp. of
diverse STs, as observed in NJ and NY, USA [24] .
KPC enzymes possess highly conserved
active-site motifs, including S-X-X-K, S-D-N
and K-T-G in class A β-lactamases  [1] . These
KPC enzymes, in contrast with other class-A
β-lactamases, possibly have a catalytic serine in
a more shallow position of the active-site cleft
according to structural analysis [25] . This spe-
cific structure might allow carbapenem agents
greater access to the catalytic site, thereby
likely facilitating acylation and deacylation
processes [25] .
408 Future Microbiol. (2015) 10(3)
KPC enzymes are only weakly inhibited by
clavulanate  [3] . However, studies showed that
KPC-positive K. pneumoniae isolates coharbor
plasmidic genes encoding for AmpC cepha-
losporinase (bla DHA and blaCMY ), extended-
spectrum β-lactamase (ESBL ; mainly
blaCTX-M) [26–28] and MβLs [26,29] . Furthermore,
bla KPC -bearing plasmids likely also carry qui-
nolone-resistant (qnrA, qnrB)  [30] , and ami-
noglycoside-modifying genetic determinants
(ArmA and RmtB)  [31] . Unsurprisingly, KPC-
producing GNB frequently exhibit multidrug-
resistant (MDR) phenotypes [17,20] , severely lim-
iting antimicrobial options. In addition, studies
have shown that KPC-K. pneumoniae isolates
have impermeable outer membranes (deficiency
of OmpK36, a porin of carbapenem entry),
which further amplifies the resistance level to
carbapenem agents [3,32] . The blaKPC genes have
also been detected in Pseudomonas aeruginosa
isolates obtained from patients in Colombia [33]
and in Acinetobacter spp. obtained from patients
in Puerto Rico [34] .
KPC-producing K. pneumoniae causes a
wide variety of infections including bacteremia,
pneumonia and urinary tract infections [17] . The
severity of those infections is highest in high-risk
patient populations, such as patients with pro-
longed hospitalization courses, those who stay
in intensive care units, and patients who receive
immunosuppressive drugs or multiple antibiotic
agents [3,17] . It is noteworthy that only a minor-
ity (<25%) of patients with infection due to
carbapenem-resistant KPC-producing K. pneu-
moniae have a history of carbapenem therapy,
while the majority have received other β-lactams
or fluoroquinolones [17] .
Variants of the KPC enzyme, first discovered in
K. pneumoniae (KPC-1) in NC in 1996 [35] , have
been detected in many Enterobacteriaceae spp.,
including E. coli, Enterobacter cloacae, S. marc-
escens, Salmonella enterica and other Klebsiella
spp.  [3,23,36–38] . During the last 10 years, there
has been a rapid and extensive spread of KPC-
producing K. pneumoniae in the northeastern
part of the USA [17,39] , the earliest epicenter of
clonal KPC strains. Other countries, including
Israel (ST258) [40] , Korea (ST258) [41] and China
(ST11, a single-locus variant of ST258) [19,31,42] ,
also have a high prevalence of KPC (type 2 or
3). Additionally, multicentre disseminations
relevant to KPC-producing K. pneumoniae have
been reported in Poland (KPC-2, ST258) [43] ,
France (KPC-2, ST258) [44] , Singapore (KPC-2,
future science group

ST11)  [42,45] , Taiwan (KPC-2, ST11) [9,26,42] ,
Cyprus  [46] and especially in Italy (KPC-2
and KPC-3, ST258/512 and other STs) [46–48]
and Greece (ST258) [29,48,49] with a striking
escalating trend of the KPC prevalence recently.
In the USA, the prevalence of KPC-bearing
bacteria was 0.15% during 2000–2005 [3,50] .
However, the KPC prevalence obtained by a
screening survey for the patients in postacute care
settings of Chicago was estimated up to be 8.3%
about 5 years ago [51] , with sevenfold greater odds
of colonization among patients being transferred
from acute care hospitals [51,52] . These figures
significantly differed from that (5.6%) of the
patients receiving mechanical ventilation in
long-term care facilities in 2010 in Maryland,
USA  [39] . The vast majority of resistant strains
bearing blaKPC genes were ST258 (except those
in China [19] , Taiwan [26] and Singapore [45] ,
with ST11 clones). The clinical facts of uninter-
rupted epidemics regarding few clones of blaKPC
genes on the patients hospitalizing in numer-
ous epidemiologically-linked healthcare institu-
tions  [16,17] re-emphasized the clonal transmis-
sibility of blaKPC-bearing K. pneumoniae isolates
with extremely high efficiency.
Rare molecular class A acrbapenemases
●●NMC/IMI & SME
The genes encoding for NMC/IMI and SME
enzymes are chromosomally located. NMC has
97% amino-acid homology with IMI-1, and
shares 70% amino-acid identity with that of
SME-1 [53,54] . For these enzymes, imipenem is
more readily hydrolyzed than meropenem. The
degree of nonsusceptibility to carbapenem is
affected by the expression of regulatory genes
(nmcR, ImiR and smeR) flanking the resistance
determinants [53–55] .
The SME enzyme, first detected in S. marc-
escens in 1982 [36] , has been implicated in only
one possible cluster in the USA [56] . Similarly,
the NMC/IMI enzymes have only been found in
E. cloacae isolates obtained from patients in the
USA and France [37,53,57] . It is unlikely that these
chromosomal genes conferring carbapenem non-
susceptibility have spread beyond the countries
listed above.
●●GES family
The genes encoding for GES enzymes are
located in integrons on plasmids. They were
formerly classified as ESBLs, but the hydrolytic
spectrum was expanded to include imipenem
future science group
Carbapenemase-producing Gram-negative bacteria  Review
(GES-2; in P. aeruginosa) in 2001 [58] . All vari-
ants of GES enzymes are distantly related to
above-mentioned carbapenemase enzymes [59] .
GES enzymes were rare and only identified in
a few European, African, American and Asian
countries  [59–62] . In addition, they were only
involved in small outbreaks of infections due to
P. aeruginosa or K. pneumoniae.
Molecular class B carbapenemases
Molecular class B metallo-β-lactamases (MβLs)
are characterized by their ability to hydrolyze
all β-lactam (including carbapenem) agents
and to confer resistance to commercially avail-
able β-lactamase inhibitors (sulbactam, cla-
vulanate and tazobactam). Nevertheless, they
are uniquely susceptible to aztreonam and are
inhibited by metallic ion chelators (such as
EDTA). The mechanism of hydrolysis mainly
depends upon interaction of β-lactam substrates
with divalent cations in the action site of these
enzymes. The considerable spread of MβL genes
is thought to be driven by increasing consump-
tion of extended-spectrum cephalosporin or
carbapenem agents [1] .
A few MβL enzymes encoded by chromo-
somal genes have been found in some oppor-
tunistic organisms, such as Bacillus cereus  [63] ,
Aeromonas spp. [64] , Elizabethkingia meningo-
septica and Stenotrophomonas maltophilia  [1,65]
after exposure to β-lactam drugs. However,
nosocomially acquired outbreaks have only been
reported for S. maltophilia and E. meningosep-
tica, indicating that horizontal gene transfer of
MβL enzymes is rare among most species that
produce MβL enzymes.
Before 2002, the overall prevalence of MβL
enzymes among GNB isolates in Japan was 0.5%
(3.0% among S. marcescens and 2.6% among
imipenem-resistant P. aeruginosa)  [66] . Since
then, however, there has been a steep increase
in the detection of acquired plasmid-mediated
MβLs. Of the transferable MβL enzymes, imi-
penemase (IMP), Verone integron-encoded
metallo-β-lactamase (VIM) and New Delhi
metallo-β-lactamase (NDM) are the most
common, while German imipenemase (GIM),
Sao Paulo metallo-β-lactamase (SPM) and
Seoul imipenemase (SIM) are endemic. With
the exception of NDM, GIM and SPM, genetic
determinants of resistance are usually incor-
porated into the cassettes of various integrons,
which facilitate their spread when they are on
plasmids.
www.futuremedicine.com 409
Review  Jean, Lee, Lam, Hsu, Chen & Hsueh
●●IMP
IMP enzymes were found on conjugative plas-
mids of clinical P. aeruginosa isolates in 1991 [67]
and then on S. marcescens in Japan in 1995 [68] .
The IMP-2-encoding genes, which reside in
a gene cassette on class 1 integrons, were first
discovered in Acinetobacter baumannii isolates
obtained in Italy in 2000 [69] . These highly
mobile integrons comprise important intrinsic
genetic determinants (integrase, recombinase
and promoter) that facilitate the expression of
associated resistance genes (bla IMP and qacE1,
sul1 gene conferring resistance to quaternary
ammonium compounds and sulfonamides,
respectively). Various kinds of IMP enzyme were
subsequently found in enteric and in glucose
nonfermentative GNB species in other coun-
tries around the world [70–72] . To date, however,
highly endemic GNB with IMP enzymes were
only reported in Taiwan (bla IMP-8 )  [73] and in
Japan (bla IMP-1) [74] .
●●VIM
Similar to blaIMP genes, the genes encoding for
VIM enzymes on K. pneumoniae are incorporated
into class 1 integrons on plasmids [75] . However,
the integrons that carry VIM genetic traits are
also capable of conjugating into the genome of
plasmids (or chromosomes) of other bacteria
(especially, Enterobacteriaceae spp.) with mark-
edly high efficiency, allowing the blaVIM genes to
rapidly spread to diverse clones of the same GNB
species or to different GNB species [4,76] . The
difference in efficiency of conjugation between
blaIMP and blaVIM genes might explain the higher
worldwide prevalence of GNB that harbor blaVIM
genes. In addition, many studies have shown that
plasmids of resistant blaVIM-harboring isolates are
able to carry other resistant traits, including KPC,
dfrA1, ESBL (blaSHV, blaCTX-M), aac(6’)-Ib, aacA7,
aadA1 [4,26,77,78] . Therefore, some blaVIM-bearing
K. pneumoniae isolates display MDR phenotypes.
The first two reported cases of infections
due to VIM-harboring GNB were in France
(VIM-2) in 1996 [79] and in Italy in 1997 [80] .
In both countries, the VIM-harboring pathogen
was P. aeruginosa. Since then, genes encoding for
various VIM enzyme variants have been found
in Pseudomonas spp., many Enterobacteriaceae
spp. (mainly K. pneumoniae, E. coli, E. cloacae
and Proteus mirabilis), and A. baumannii in a few
European countries (principally VIM-1, VIM-2
and VIM-5), Turkey (VIM-5), Tunisia, the USA,
Korea (VIM-2), Japan (VIM-2), Taiwan (VIM-3)
410 Future Microbiol. (2015) 10(3)
and some countries in South America (mainly
VIM-2)  [49,75,77,81–84] . A European surveillance
study reported that infections caused by blaVIM-1
cassette-bearing GNB had reached an epidemic
status in Greece in 2010 [85] , making that country
a potential epicenter of blaVIM, blaKPC-2 (ST258)
and bla NDM-1 gene transmission. The KPC-
producing K. pneumoniae strains have prevailed
in many healthcare institutions in Mediterranean
countries nowadays [29,86] . In Taiwan, a surveil-
lance study of anti­microbial resistance during the
period of 2000–2002 showed that the prevalence
of MβL genes ranged from 17 to 36%, and VIM-3
was the most common (88%) MβL enzyme in P.
aeruginosa isolates that showed nonsusceptibil-
ity to antipseudomonal carbapenem agents [87] .
The prevalences of MβL genes in P. aeruginosa
isolates collected during 2000–2002 and 2010
(18.3%; all were VIM) [88] in Taiwan were promi-
nently higher than that reported in a surveillance
conducted in France in 2010 (6.4%) [89] .
There is a great variation in MIC values of car-
bapenems against blaVIM-carrying K. pneumoniae
strains [75] . Loli et al. found that a high degree of
expression of plasmidic blaVIM genes (after rear-
rangement, generated by IS26 ) combined with
loss of Omp porin is required to confer high
MIC levels against carbapenem agents [90] . In
addition, the increasing consumption of some
antibiotics (primarily carbapenem agents [78] , as
well as extended-spectrum cephalosporins [91])
might potentially select the emergence of clini-
cal blaVIM-bearing GNB isolates with high-level
resistance to carbapenem drugs.
Pseudomonas aeruginosa isolates, with gradu-
ally increasing rates of nonsusceptibility to many
important antibiotics since last decade [92,93] ,
were notorious to possess many resistance
mechanisms and ever involved in an outbreak
due to the VIM-1 producers [94] . In addition
to efflux pumps, membrane impermeability,
AmpC and ESBL [92] , the bla IMP-2 and bla IMP-13
genes have been detected on P. aeruginosa iso-
lates from Japan [95] , Italy [96] more than 10 years
ago. Of clinical note, these VIM-2-producing
P. aeruginosa isolates have been implicated in
a number of serious infections that are refrac-
tory to imipenem therapy, including septicemia,
pneumonia, urinary tract and intra-abdominal
infection and miscellaneous entities [75,97] . In
addition, in Riyadh and Mecca, high prevalence
rates of P. aeruginosa isolates harboring the VIM
determinants (16–20%) and IMP traits (23%)
were also reported [98] .
future science group

Clinically, Daikos et al. investigated the
prognosis of 28 patients with infection due to
blaVIM-1-bearing GNB and found that patients
with bloodstream infections caused by the
VIM-1-producing K. pneumoniae with the imi-
penem MIC >4 mg/l have a higher mortality
rate (60%) than those with infections due to
VIM-1-producing K. pneumoniae that has an imi-
penem MIC ≤4 mg/l (14.3%) or those infected
with non-blaVIM K. pneumoniae  [99] . They also
noted that patients with rapidly fatal underlying
diseases or higher degrees of clinical severity are
more likely to die in the hospital setting [99,100] .
●●NDM
NDM enzymes were first detected in 2010 in
patients transferred from the Indian subconti-
nent, an overcrowded region where antimicro-
bial usage is poorly regulated [11,48] . Accumulated
evidence has pointed out that dissemination of
the bla NDM traits is difficult to be predicted.
For instance, it is noteworthy that the in vivo
transfer of bla NDM-1 determinants was proven
between different Enterobacteriaceae spp. (K.
pneumoniae and E. coli) in the same patient,
as described by Yong et al.  [101] . Furthermore,
one survey exploring the genetic environments
of bla NDM-1-carrying E. coli strains in China
showed that the blaNDM-1 genes were flanked by
some unique elements (IS3000, ISAba125, IS26
and a transposase gene), which suggests that a
horizontal blaNDM-1 transfer potentially assisted
by mobile transposons likely happened between
E. coli and possibly environmental Acinetobacter
spp. [102] . In addition, the other important inves-
tigation by Kumarasamy et al. revealed that the
bla NDM-1 genes on Enterobacteriaceae spp. from
the northern India were not conjugated, with
these resistant isolates being of an identical clon-
ality, which posed a significant contrast with
the NDM-1 genes being readily transferable on
clonally few diverse isolates (with plasmids of
various sizes) collected from the southern part of
India (as well as from the UK) [11] . The house-
hold contacts also likely facilitate to spread the
bla NDM-1 alleles, as seen in an Australian child
never traveling abroad [103] . In New Delhi, many
other blaNDM-1-harboring bacteria were discovered
from the drinkable tap water [48,104] , rendering
them listed as potentially community-acquired
pathogens. Consequently, the pattern about dis-
semination of NDM-1 genes is apparently com-
plex, thereby posing an immense challenge on
infection control [105] .
future science group
Carbapenemase-producing Gram-negative bacteria  Review
Unlike blaVIM and blaIMP, the spread of blaNDM
genes is not assisted by integrons [1,105] . The pos-
sible mechanisms governing plasmid-induced
spread of the blaNDM traits include the reshuffling
of blaNDM-bearing cassettes on various integrons of
plasmids, and the en bloc mobilization of blaNDM-
associated segments in a manner involving recom-
bination or transposition, with probable assistance
by some insertion elements, such as IS26, ISEc33
or ISSen4 [1,11,106–108] . Thus, the blaNDM-1 genes vir-
tually move with a slow pace on plasmids [15,109,110] .
Recently, bla NDM-1 genes, via spread of Tn125,
have also been identified in clinical isolates of A.
baumannii [111] . In striking contrast to blaVIM and
blaIMP genes, blaNDM-1 genes were rarely detected
in clinical isolates of P. aeruginosa [112] .
Plasmids carrying blaNDM-1 genes also coharbor
other resistance genes encoding for other carbap-
enemases such as class D oxacillinases (e.g., OXA-
48-like β-lactamases and VIM types), plasmidic
AmpC cephalosporinase, ESBL enzymes (mostly
CTX-M), qnrA6, qnrB1 and the genes responsible
for resistance to macrolide (esterase), sulfameth-
oxazole, rifampicin and aminoglycoside [11,15,109] .
Unsurprisingly, most bla NDM-1-bearing GNB
exhibit an MDR profile. One in vitro study showed
that aztreonam-avibactam (formerly known as
NXL104) combination has promising potential
against some Enterobacteriaceae species producing
MβLs [113] . Nevertheless, the therapeutic regimens
proven effective against NDM-producing organ-
isms are unknown nowadays [11,114] .
NDM-1 enteric GNB producers have been
reported in most continents, except the Central
and South America [15,115,116] . The number of
reports on patients carrying the blaNDM-harboring
Enterobacteriaceae spp. in Australia is increasing
recently  [104,107,117,118] . Additionally, the United
Arab Emirates (7% of in-hospital K. pneumoniae
isolates having bla NDM-1) and Balkan countries
have become the second reservoirs of bla NDM-1
unlinked to pandemics of the Indian subconti-
nent [87,97,119,120] . It is noteworthy that the patients
infected or colonized with blaNDM-positive GNB
without a definite link to the Indian epidemics
have gradually increased in a few countries [121] .
NDM-1-producing isolates of A. baumannii
have also been identified worldwide, with the
exception of countries in Central and South
America  [111,122] . Thus, physicians should be
also aware of a possible epidemic of infections
caused by bla NDM-1-harboring A. baumannii.
A scheme of important gene sequences that
contain genetic traits encoding for important
www.futuremedicine.com 411
Review  Jean, Lee, Lam, Hsu, Chen & Hsueh

carbapenemases (classes A, B and OXA-48) is horizontal gene transfer. Nevertheless, they were
illustrated in Figure 1. not reported elsewhere.

●●SPM, GIM & SIM Molecular class D carbapenemases: the

SPM-1 was first identified from clinical P. aer-
uginosa isolates in Sao Paolo, Brazil in 2004 [123] .
Genetic analysis of blaSPM-1 revealed that these genes
were not part of the integron but were on trans-
posons (comprising recombinase and promoter,
among others). Therefore, blaSPM-1 also has the
potential to cause nosocomial outbreaks [123,124] .
In contrast, the GIM-1 enzyme was found on non-
transferable plasmids of P. aeruginosa in Germany
in 2002 [125] , and has more recently been found in
Enterobacteriaceae spp. [126,127] . The blaSIM-1 genes
were discovered on class 1 integrons of A. bau-
mannii in Korea [128] , indicating the potential for
OXA β-lactamases
Clinical isolates of carbapenem-resistant A. bau-
mannii (CRAB; mostly with MDR phenotype)
that harbor acquired genes encoding for various
class D carbapenemases have resulted in numer-
ous nosocomial outbreaks with high (>30%)
mortality rates in hospitalized patients [129] and
in septicemia in injured US military personnel
who served in Iraq and Afghanistan from 2003
through 2005 [130] . The OXA β-lactamases, func-
tionally defined as penicillinases capable of hydro-
lyzing cloxacillin and oxacillin [131] , were initially
identified in the late 1970s. Despite considerable

KPC (I) (Tn4401)

IRL tnpR tnpA ISKpn7 blaKPC-2 ISKpn6 IRR orf5
VIM (II)
IS26 int1 blaVIM-1 aacA7 dfrA1 aadA1 gacE sul1 IS26 Tn1721 Tn2

(III)
IS5075 Tn1696 int1 blaVIM-1 aacA7 dfrA1aadA1 smr ISpa21

IMP (IV)
IS26 int1 blaIMP-8 aacA4 TniC

NDM (V)
ISAba125 blaNDM-1 bleMBL IS26 Tn3

(VI)
ISEc33 ISAba125 blaVIM-1 bleMBL ISSen4
OXA-48 Tn1999

(VII)
IS1999 blaOXA-48 IS1999

(VIII)
IS4321 Tn3 blaOXA-163 IS4-like

Figure 1. Schematic illustration of sequences of important genetic components and their

orientations from plasmids of various Enterobacteriaceae spp., which show the association of
important carbapenemase (Ambler class A and B)-encoding genes with various mobile elements.
(i) The blaKPC-2-containing Tn4401 transposon, from plasmid pNYC (GenBank accession no. EU176011).
(ii & iii) Representative blaVIM-containing sequences from plasmid pNL194 (GenBank accession
number: HQ651093) and pCC416 (GenBank accession number: AJ704863), respectively. (iv) The
blaIMP-containing sequence from plasmid pFP10-2 (GenBank accession number: 651093). (v & vi) The
blaNDM-1-containing sequences, carried by a plasmid from K. pneumoniae 05-506 (GenBank accession
number: FN396876) and plasmid p271A (GenBank accession number: HQ162469). (vii & viii) The
OXA-48-encoding transposon Tn1999 from plasmid pA-1 (GenBank accession number: 236073)
and blaOXA-163-containing segment from plasmid p6299 (GenBank accession number: HQ700343),
respectively. The two kinds of star symbol within sequences highlight locations of the genes that
encode for carbapenemase enzymes. The underlined genetic components represent the ones with
deletion of partial genes, and the black-filled rectangles denote genes of unknown function.
 Adapted with permission from [122].

412 Future Microbiol. (2015) 10(3) future science group


variability in amino-acid sequences [1] , they are
characteristically not inhibited by clavulanate
or EDTA.
The first OXA β-lactamase that could hydro-
lyze carbapenem was identified on a large plasmid
of MDR-A. baumannii in Scotland in 1985 [132] .
It was categorized as OXA-23 enzyme of Ambler
class D after gene sequencing [133] . Since then,
OXA carbapenemases have been found in a
number of clinical isolates of A. baumannii that
display resistance to imipenem [134–137] . Of note,
Héritier et al. found that after transformation of
plasmids carrying blaOXA-23, blaOXA-40, or blaOXA-58
genes into imipenem-susceptible A. bauman-
nii recipient strains, the OXA-23 and OXA-40
enzymes in A. baumannii would render originally
susceptible isolates intermediate resistance to imi-
penem  [138] . Although efflux pumps [138] , porin
deficiency  [139] and hyperproduction of AmpC
cephalosporinase  [140] contribute to high-level
resistance of A. baumannii to carbapenem agents,
class D β-lactamases are still considered the most
important cause of nonsusceptibility to carbap-
enems. It is also noteworthy that K. pneumoniae
isolates harboring plasmidic blaOXA-48 genes have
been detected [141] .
The catalytic mechanism of some OX A
enzymes shares similar features to class A ser-
ine carbapenemases, although the hydrolytic
efficiency against carbapenems is weaker for
the former [1] . Amino-acid sequence analysis of
both class A and D enzymes has revealed that the
catalytic serine residue lies in the S-T-F-K tetrad
at positions 70 to 73, where serine and lysine resi-
dues are well conserved [142] . Although variability
of sequences on the Y-G-N motif (positions 144
to 146) and the K-T-G triad motif (positions 216
to 218) was found between different variants of
the OXA enzyme in class D β-lactamases [1,143] ,
variants of OXA-23, -24, -25, -26 and -27 shared
the S-T-F-K tetrad and S-X-V triad motifs.
Furthermore, based upon the analysis of crystal
structure of OXA enzymes, β-lactam drugs are
hydrolyzed through the process of formation of a
covalent acyl intermediate (carbamate) between
a β-lactam substrate and the OXA enzyme, with
subsequent deacylation [144] .
●●OXA-23-like, OXA-24-like & OXA-58
According to amino-acid sequence analyses, the
OXA-27 and OXA-49 enzyme variants share
high amino-acid identities with that of OXA-23,
thus all of them were classified as the blaOX A-
23-like
genes. In contrast to the second group of
future science group
Carbapenemase-producing Gram-negative bacteria  Review
acquired class D β-lactamases, in other words,
OXA-58-like enzymes (comprising OXA-58
and OXA-96) [145] , a third group of acquired
class D oxacillinases, consisting of OXA-24/40,
OXA-25, OXA-26 and OXA-72 because of
similar amino-acid arrangements, was identi-
fied in A. baumannii isolates with a carbapenem-
resistant phenotype. They were categorized as
blaOXA-24-like genes after sequencing [143,146] .
Compared with the blaOXA-51-like genes located
on the chromosomal genome [147] , the blaOXA-23
genes are usually located on plasmids and have
high transferable potential when combined with
transposon Tn2006, Tn2007 or Tn2008  [5,6] .
The blaOXA-23 genes are flanked by two copies of
insertion sequences, in other words, ISAba1 (one
member of the IS4 family) in opposite direc-
tions on transmissible transposon Tn2006 and
Tn2008 [6,7] . By contrast, the transposon Tn2007
lacks the second copy of ISAba1, and instead its
blaOXA-23 genes are associated with one copy of
ISAba4 (belonging to the IS982 family) [6] . These
transposons confer A. baumannii medium-to-
high resistance against antipseudomonal carbap-
enem agents (MIC ≥16 mg/l) and ceftazidime [12] .
Acquisition of these composite and highly trans-
missible transposons by clinical A. baumannii iso-
lates, which subsequently reside on their chromo-
somal or plasmidic genome, might theoretically
result in a resistance epidemic if appropriate meas-
ures of infection control are not taken [5,7,12,14] .
As seen in the blaOXA-23 genes, many acquired
insertion sequences (ISAba1, ISAba2, ISAba3-
like element, IS1008 and IS18) have been shown
to provide a promoter involved in the overex-
pression of plasmidic blaOXA-58 genes in A. bau-
mannii and A. nosocomialis  [148,149] . However,
Poirel et al. hypothesized that high-level carbap-
enem resistance happens after a series of step-by-
step recombination events rather than simply the
acquisition of an integron or transposon [148] . In
addition, the results of an in vitro electrotrans-
formation experiment of oxacillinase genes in
A. baumannii isolates revealed that OXA-23 has
higher imipenem hydrolytic capacity than OXA-
58  [138] . In contrast to blaOX A-23 and blaOX A-58
genes which can be on either plasmid or chro-
mosome, blaOXA-24-like genes are mainly located
on chromosomes and no mobile elements have
been identified [150] .
Polyclonal dissemination of CRAB isolates
harboring the blaOXA-23 genes has been reported
in Brazil [134] , China [13] , South Korea [151] ,
French Polynesia [5] , Bulgaria [152] , Algeria [153] ,
www.futuremedicine.com 413
Review  Jean, Lee, Lam, Hsu, Chen & Hsueh
the Kingdom of Saudi Arabia [119] , central
Taiwan  [154] and the United Kingdom [135] .
During the last decade, the SENTRY program
investigated the spread of oxacillinase genes
among species of Acinetobacter collected from
Asia-Pacific nations. That surveillance study
revealed that the blaOXA-23 genes were common
in Acinetobacter spp. (>90% of which were
A. baumannii, and >40% of which were nonsus-
ceptible to imipenem or meropenem) in China
and in other countries [13] . In addition, 41% of
blaOX A-23 -bearing Acinetobacter isolates cohar-
bored the blaOXA-58 genes [13] . These findings were
consistent with those reported by Mugnier et al.,
who found that a dynamic worldwide spread of
the blaOX A-23 genes on plasmids of polyclonal
A. baumannii strains occurred in 2010 [12] .
In contrast, the blaOXA-58-like genes, which are
far more prevalent than the blaOXA-23-like genes in
A. baumannii isolates in many European coun-
tries [155] , has also been detected on Acinetobacter
spp. in Argentina and Kuwait [156,157] . In addi-
tion, OXA-24 enzyme variants in A. bauman-
nii have been identified in outbreaks in Spain,
Portugal, Belgium and the USA [136,146,155,158] .
●●OXA-48
The OXA-48 enzyme, along with OXA-54,
OXA-181, were identified in Shewanella oneiden-
sis (a natural carrier of the progenitor blaOXA-48-like
genes)  [159] , as well as K. pneumoniae  [141] and
other enterobacteria [8,159] . In contrast to KPC,
the hydrolysis of carbapenems for OXA-48 car-
bapenemase needs the rotation of carbapenem’s
α-hydroxyethyl group within the active site [122] ,
which plausibly explains its weaker hydrolytic
capacity against imipenem than that of KPC.
It is noteworthy that the blaOXA-48-like traits are
carried by transferable transposon Tn1999 (or
Tn1999.2) on plasmids, which confers medium-
to-high spread potential [1,8] . In fact, the in vitro
hydrolytic efficiency of OXA-48 itself against
imipenem is approximately tenfold higher
than that of other oxacillinases in Acinetobacter
spp.  [160] . In addition, enteric GNB with the
blaOXA-48-like genes could coharbor genes encod-
ing for ESBL (blaCTX-M, blaSHV, blaTEM) or AmpC
enzymes, or both [8,161] , thereby conferring non-
susceptibility to aztreonam, extended-spectrum
cephalosporins and carbapenem agents.
Because of their specific location on plasmids,
the worldwide spread of blaOX A-48-like genetic
determinants is not surprising. Isolates of blaOXA-
48
-bearing K. pneumoniae were initially identified
414 Future Microbiol. (2015) 10(3)
in Turkey [141] , subsequently in a number of coun-
tries of the Middle East [8] , North Africa [162] and
Western Europe (UK, Belgium, France, Germany,
Netherlands)  [48,85] . India [163] , Senegal [161] ,
Spain  [48,164] and Argentina [165] have also iden-
tified the OXA-48-producing Enterobacteriaceae
species other than K. pneumoniae. Although the
KPC-2, NDM-1 and VIM-2 carbapenemases
dominated in Greece, an outbreak due to the
blaOXA-48-harboring K. pneumoniae isolates of
ST11 clone was also reported in 2012 [166] . Thus,
a global dissemination of blaOXA-48-carrying GNB
has emerged. The sites of worldwide distribution
regarding high regional prevalences of GNB har-
boring various kinds of important carbapenemases
are illustrated in Figure 2.
Antimicrobial treatment of infections due
to carbapenemase-producing organisms
Experience using antimicrobial therapy against
infections caused by carbapenemase-producing
GNB is limited.
●●Enterobacteriaceae
Against the KPC-producing K. pneumo-
niae isolates with doripenem MIC ≤16 mg/l,
Wiskirchen  et al.  [167] demonstrated that the
dual-carbapenem regimen (standard-dose ertap-
enem as the high-affinity substrate of KPC [168] ,
followed by doripenem 2 g every 8 h with 4‐h
infusion intravenously) would significantly
reduce the bacterial density (but not to a bacte-
ricidal level, as compared with control or respec-
tive monotherapy groups) in the murine thigh
in vivo model. However, its clinical efficacy on
humans needs to be investigated. By contrast,
colistin and tigecycline used to be considered
the drugs of choice for treating infections due to
carbapenemase-producing GNB, and especially
for GNB of KPC and MβL producers [50,169] .
Unfortunately, extensive usage and the spread
of resistant clones have resulted in a consider-
able drop of the in vitro susceptibilities to these
two antimicrobial agents [170,171] . Resistance to
colistin is notably more frequent among carbap-
enem-resistant K. pneumoniae than in MDR-
P. aeruginosa and MDR-A. baumannii  [172] . To
maximize the clinical effectiveness of colistin
against impending resistant GNB (colistin MIC,
2 mg/l), studies have shown that the loading and
maintenance doses should be increased [173] . In
addition, tigecycline is merely a bacteriostatic
agent with suboptimal concentrations in the
bloodstream (<2 mg/l) and epithelial lining fluid
future science group
 Carbapenemase-producing Gram-negative bacteria  Review

Greece
VIM-2, NDM-1 Turkey
KPC-2 OXA-48 USA
China
KPC-2
KPC-2 South korea
UK KPC-3
OXA-23 VIM-2, IMP,
NDM-1
KPC-2, OXA-23
Israel
Germany KPC-2
OXA-48 Middle East
OXA-48

Japan
Italy IMP-1
KPC-2, 3 South America
OXA-48 VIM-2, OXA-48,
OXA-58 Taiwan OXA-23
KPC-2, IMP-8
VIM-3, OXA-23
North Africa Saudi Arabia
South Europe India
VIM, OXA-23
VIM-1, 2, 4, 5 NDM-1
OXA-48 OXA-48
OXA-58

United Arab
Emirates
NDM-1 Australia
IMP-4, NDM-1

Figure 2. Global distribution of high regional prevalences of contemporary Gram-negative bacilli possessing important
carbapenemases.

(<0.50 mg/l) of human pulmonary tissue under
standard-dose regimens [42,174] . Furthermore,
although gentamicin and fosfomycin have high
in vitro susceptible rates against some carbapen-
emase (KPC and VIM, among others)-producing
Enterobacteriaceae spp. [175,176] , these agents should
only be used as a combination option against crit-
ical infections caused by carbapenemase-produc-
ing GNB because of potentially rapid induction
of resistance after monotherapy [169,177] .
Despite some controversies [175] , combination
therapies have been shown to result in favora-
ble outcome in patients with infections due to
carbapenemase-producing GNB. A combination
of doripenem with colistin has been reported to
have excellent in vitro synergistic effects against
KPC-producing K. pneumoniae isolates [178] . A
tigecycline-colistin combination was shown to
be superior to colistin monotherapy in decreas-
ing resistance to colistin [179] . Notwithstanding
these in vitro synergy data supported use of
combination regimens, the well-designed clini-
cal randomized control trials that strictly inves-
tigated which antimicrobial schemes are effec-
tive against the infections due to KPC-producing
isolates virtually lack till now. For example, in a
retrospective cohort study on 41 patients with
KPC-producing K. pneumoniae bacteremia,
Qureshi et al. found that combination therapies
(carbapenem agent combined with colistin or
tigecycline) would result in significantly lower
case-fatality rates (odds ratio: 0.07 [95% CI:
0.009–0.71]; 28‐day mortality rate: 13% [1/8
died] for combination group vs 67% for colistin
or tigecycline monotherapy [4/7 and 4/5 died,
respectively])  [180] , despite all of the MIC levels
of colistin or tigecycline against KPC-K. pneu-
moniae isolates from monotherapy (using either
of the above two agents) patient group fell within
the susceptible range in accordance with the crite-
ria of CLSI 2011 [181] or US FDA (contrasting the
carbapenem MICs being ≥2 mg/l for all isolates

future science group www.futuremedicine.com 415

Review  Jean, Lee, Lam, Hsu, Chen & Hsueh
from the remaining four monotherapy patients,
with 50% mortality) [180] . The analogous find-
ings agreed well with a recent systematic review
on the outcome of 432 patients with bloodstream
infections caused by carbapenemase-producing
K. pneumoniae  [182] . In addition, a systematic
review performed by Lee et al. [183] revealed that
some combination schemes (colistin with carbap-
enem, tigecycline or aminoglycoside) had equally
favorable clinical outcomes, and compared with
other patient groups, the pneumonic subgroup
was particularly associated with a higher mortal-
ity rate than other subgroups when monotherapy
was employed. Tumbarello et al.  [184] retrospec-
tively analyzed the outcome of 125 patients
with bloodstream infections caused by KPC-
producing K. pneumoniae from three large Italian
hospitals. Regardless of meropenem MICs (≤4 vs
>4 mg/l), they found that a triple-drug combina-
tion regimen comprising tigecycline, colistin and
meropenem was notably associated with better
survival rates (87%) than monotherapy (58%).
It is noteworthy that the clinical efficacy of this
triple-drug combination scheme still exists even
when the meropenem MICs of KPC-K. pneumo-
niae isolates were up to 16 mg/l [184] . With respect
to the bloodstream infections due to blaVIM-pos-
itive K. pneumoniae isolates, Daikos et al.  [100]
found that dual-drug therapy (carbapenem plus
colistin or aminoglycoside) was associated with
significantly lower patient mortality rates than
monodrug group (8.3 vs 27–29%).
In addition, a systematic review performed by
Tzouvelekis et al.  [122] investigated the outcome
of 298 patients (from 34 studies) with serious
infection (bacteremia and/or pneumonia) due
to carbapenemase-producing Enterobacteriaceae
spp. (158 KPC, and 140 MβL). Therapeutic
regimens were divided into monotherapy (only
one in vitro active agent), combination therapy
(≥2 in vitro active drugs) and inappropriate (all
were in vitro nonsusceptible drugs) groups. This
review reveals that the combination therapy con-
taining carbapenem plus colistin (or an amino-
glycoside) results in lower case-fatality rates (5.5
and 6.2%, respectively) than other treatment
modalities (>23%) [122] . Finally, the other recent
large-scale survey [185] retrospectively investigated
the impact of different antimicrobial regimens
on clinical outcome regarding the bloodstream
infections caused by carbapenemase-produc-
ing K. pneumoniae isolates collected from 205
patients (79.5% due to KPC, or KPC plus VIM
variants) in great details. In this survey, the MIC
416 Future Microbiol. (2015) 10(3)
breakpoints recommended by the European
Committee on Antimicrobial Susceptibility
Testing (EUCAST) in 2013 (of which the MIC
judgment criteria categorized as resistant for imi-
penem, meropenem and doripenem being >8, >8,
>4 mg/l, respectively) were applied for determin-
ing the nonsusceptibilities [186] . Independence
of the declining stages of sepsis and underlying
comorbidities, they also observed that combina-
tion therapy is significantly superior to mono-
therapy on 28‐day mortality rate (27.2 vs 44.4%,
p = 0.018), particularly for the regimen consisting
of a carbapenem with the MIC ≤8 mg/l and the
other in vitro active agent (achieving the low-
est case-fatality rate, 19.3%). This carbapenem
MIC limit (8 mg/l) verified to confer benefits on
survival is similar to the pharmacodynamic (PD)
features of carbapenems [187,188] , and is exactly
the same as the MIC breakpoints of EUCAST
2013 [186] . Of note, in the sub-analysis regarding
the impact of in vitro activity of drug(s) employed
in conjunction with carbapenem(s) on clinical
outcome, the therapeutic benefit provided by car-
bapenem agent was prominently compromised
once carbapenem was combined with inactive
drug(s)  [185] . The advantage of carbapenem-
containing combination regimens on decreas-
ing case-fatality rates (18.8%, as compared with
30.7% for carbapenem-sparing schemes) of
sepsis caused by the carbapenemase (primarily
KPC and VIM)-producing Enterobacteriaceae
is also seen in one latest systematic review by
Tzouvelekis et al.  [114] . In addition to receipt of
inadequate antimicrobial therapy initially [184] ,
the independent predictors of mortality about
the infections due to carbapenemase-producing
enterobacteria also included: high clinical sever-
ity (including septic shock) [184,185] , and presence
of any underlying comorbidity [185] .
Studies have shown that avibactam, a bridged
diazabicyclo octanone, exhibits good activity
against GNB with serine β-lactamases (espe-
cially KPC producers) when combined with
ceftazidime, but is inactive against class B
β-lactamases [122,189,190] . Evidence derived from
murine models also reveals that a ceftazidime-
avibactam regimen is effective against infec-
tion due to KPC producers [191] . The other
β-lactamase inhibitor, MK-7655, in vitro poten-
tiates imipenem against Enterobacteriaceae spp.
with KPC production plus membrane imperme-
ability  [192] . Hence, it is also a future promis-
ing drug effective against enteric GNB which
produce class A carbapenemases.
future science group
 Carbapenemase-producing Gram-negative bacteria  Review

Table 1. Summary of transmission medium (regarding assistance by transposon, or integron or none) and dissemination mode
(significant polyclonality versus limited diverse clones) of various kinds of important carbapenemases.
Transmission medium, Mobile transposon assistance No proven mobile transposon association
dissemination mode    With integron Without identified integron
Significant polyclonality OXA-23-like (Tn2006, Tn2007, Tn2008) VIM OXA-58-like
  OXA-48 (Tn1999, 1999.2)     
Possible limited diverse KPC, limited in K. pneumoniae (Tn4401, or variants in other species) IMP NDM traits
clones
  NDM-1    OXA-24-like
The spread of resistance genes assisted by transfer of plasmids is also seen in the blaKPC-harboring [24] Enterobacteriaceae species, and assisted by an identically clonal expansion
for the blaNDM-carrying enteric GNB isolates [11].
IMP: Imipenemase; KPC: Klebsiella pneumoniae carbapenemase; NDM: New Delhi metallo-β-lactamase; VIM: Verone integron-encoded metallo-β-lactamase.

●●Acinetobacter spp. international transport of patients with infections

Nosocomial A. baumannii isolates have many
intrinsic resistance mechanisms [150] . Clinically,
monotherapy used for treating a susceptible
A. baumannii isolate has great potential to select
the emergence of resistant strains during therapy.
Only few clinical studies confirmed that com-
bination therapy prominently improves survival
of patients with CRAB bacteremia (treated by
antipseudomonal carbapenem plus sulbactam or
aminoglycoside), serious respiratory tract infec-
tions due to extensively drug-resistant (XDR)
A. baumannii (treated mainly by doripenem
plus colistin) [193,194] , while one recent survey
revealed that patients with XDR A. baumannii
infection only got the benefit of microbiological
eradication when treated with rifampicin plus
colistin as compared with colistin monother-
apy  [195] . Additionally, high-dose sulbactam
plus infusion of meropenem at maximal dosage
(2 g every 8 h) for an extended duration (≥3 h)
was reported as effective treatment for venti-
lator-associated pneumonia due to XDR- and
CRAB by a PD assessment, if the meropenem
MIC were ≤8 mg/l [187] . An in vitro combination
of dual antibiotics (involving rifampicin, levo-
floxacin, azithromycin, doxycycline, amikacin,
sulbactam, imipenem, meropenem, tigecycline
and colistin) was investigated using a checker-
board titration method and the result showed
that there was no evidence for antagonism [196] .
Conclusion
The transmission media and dissemination modes
of various kinds of important carbapenemases in
GNB are summarized in Table 1. As the aging pop-
ulation and recipients of organ transplantation or
chemotherapy increase gradually, these immuno-
suppressed hosts have made carbapenemase-pro-
ducing GNB evolving into common community-
acquired bacteria [48] . Moreover, interhospital and
due to GNB that harbor resistance determinants
have fueled the unstoppable rise of antimicrobial
resistance. The threat of pandrug resistance has
considerably lowered the appropriateness of empir-
ical antibiotic therapy recommended by infectious
disease experts. In addition to reinforcement of
infection control measures [52] , the development
of new antibiotics is warranted to combat against
these troublesome GNB in the future.
Future perspective
The spread routes of the resistance genetic traits
encoding for carbapenemases, especially for
KPC, VIM, NDM and some OXA variants,
are complex and difficult to be completely pre-
vented. Therefore, reinforcement of infection
control tasks, along with in-time initiation of
diagnostic works regarding early detection of
the carbapenemase-producing GNB in health-
care settings, are of utmost importance. Once
infections due to carbapenemase (KPC and
VIM)-producing GNB isolates are encountered,
we recommend combination schemes, particu-
larly carbapenem (when the MIC ≤16 mg/l)-
containing regimens, as the most preferred
therapeutic regimens. Although controversy
exists, combination regimens are also favored
to effectively treat the infections caused by
XDR-A. baumannii isolates.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial
involvement with any organization or entity with a finan-
cial interest in or financial conflict with the subject matter
or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or
options, expert testimony, grants or patents received or
pending, or royalties.
No writing assistance was utilized in the production of
this manuscript.

future science group www.futuremedicine.com 417

Review  Jean, Lee, Lam, Hsu, Chen & Hsueh

EXECUTIVE SUMMARY
Klebsiella pneumoniae carbapenemase
●● Transmission via transposons, or plasmids that harbor the blaKPC traits.
●● Primarily reported in worldwide Enterobacteriaceae spp., except Australia, and the countries in Africa and South America.
●● Usually pandrug-resistant (PDR) phenotype. Carbapenem-containing regimens are preferred for treatment of the
Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae species if the carbapenem MIC value is ≤16 mg/l.
Otherwise, other alternatives could also be considered.
Verona integron-encoded metallo-β-lactamase
●● Transmission via integrons between Enterobacteriaceae spp., but the transmission between Pseudomonas spp. remains
unknown.
●● Less frequently reported in Australia and China.
●● Sometimes PDR phenotype. Therapeutic recommendation is similar to that of the Klebsiella pneumoniae
carbapenemase. The bloodstream infection due to blaVIM-1-carrying, imipenem MIC >4 mg/l K. pneumoniae isolates
predicts a high case-fatality rate.
New Delhi metallo-β-lactamase
●● Transmission media and spread modes are more complex than above two.
●● Reported in worldwide countries except those in Central and South America.
●● Usually PDR phenotype. The treatment recommendation is lacking till now.
OXA-48-like carbapenemase
●● Transmission primarily via transposons.
●● Reported in Turkey, Argentina, a few countries in the Western Europe, and especially in the Middle East, South Europe
and North Africa (surrounding the Mediterranean Sea).
●● Sometimes PDR phenotype. The therapy recommendation still lacks now.
OXA-23 & OXA-58-like carbapenemases
●● Transmission via transposons with specific insertion sequences.
●● Reported primarily in the countries of Asia-Pacific region, Europe, South America (Brazil) and North Africa.
●● Usually PDR phenotype. Combination regimens are favored, although they were only supported by in vitro synergy
tests predominantly.

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