Clinical Infectious Diseases

SUPPLEMENT ARTICLE

Epidemiology and Diagnostics of Carbapenem Resistance

in Gram-negative Bacteria
Patrice Nordmann,1,2,3,4 and Laurent Poirel1,2,3
1
Medical and Molecular Microbiology Unit, Department of Medicine, Faculty of Science and Medicine, 2Institut National de la Santé et de la Recherche Médicale European Unit, and 3Swiss
National Reference Center for Emerging Antibiotic Resistance, University of Fribourg, and 4Institute for Microbiology, University of Lausanne and University Hospital Centre, Lausanne, Switzerland

Carbapenem resistance in gram-negative bacteria has caused a global epidemic that continues to grow. Although carbapenemase-

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producing Enterobacteriaceae have received the most attention because resistance was first reported in these pathogens in the early
1990s, there is increased awareness of the impact of carbapenem-resistant nonfermenting gram-negative bacteria, such as Acinetobacter
baumannii, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia. Moreover, evaluating the problem of carbapenem resist-
ance requires the consideration of both carbapenemase-producing bacteria as well as bacteria with other carbapenem resistance
mechanisms. Advances in rapid diagnostic tests to improve the detection of carbapenem resistance and the use of large, population-
based datasets to capture a greater proportion of carbapenem-resistant organisms can help us gain a better understanding of this
urgent threat and enable physicians to select the most appropriate antibiotics.
Keywords.  Acinetobacter baumannii; carbapenemases; carbapenem-resistant Enterobacteriaceae; gram-negative bacteria;
Pseudomonas aeruginosa.

Carbapenem resistance in gram-negative bacteria has become caused by nonfermenters because of the low permeability of the
a worldwide problem. The 2017 World Health Organization outer bacterial membrane to several antibiotics, including, but
(WHO) global priority list of pathogens ranks carbapenem- not limited to, the carbapenems [11, 12].
resistant Enterobacteriaceae (CRE), carbapenem-resistant The concerns surrounding CRE-related infections [2, 13]
Pseudomonas aeruginosa, and carbapenem-resistant have recently been mitigated to some degree by the approval
Acinetobacter baumannii in the highest priority category (ie, of new β-lactam–β-lactamase inhibitor combination therapies,
critical) [1]. To address this global epidemic, identification and which demonstrate activity against strains with specific under-
ongoing surveillance of carbapenem-resistant gram-negative lying resistance mechanisms [14]; however, on-therapy resist-
bacteria are needed. ance has already been reported [15]. The use of older agents,
Evidence suggests that patients who are infected by such as tigecycline or colistin, is frequently associated with
carbapenem-resistant pathogens have an increased likelihood unclear efficacy and/or toxicity issues [11]. It is clear that un-
of morbidity and mortality compared with those infected by derstanding specific mechanisms underlying carbapenem re-
susceptible pathogens [2–4], which is likely due to administra- sistance and monitoring local epidemiology would lead to
tion of antibiotics with suboptimal or no activity against these more effective treatment of infections caused by carbapenem-
organisms [5]. Thus, recognizing the risk of carbapenem resist- resistant gram-negative bacteria.
ance [6], particularly in the most vulnerable patient populations
[5, 7–9], and/or early detection of specific carbapenem resist- MECHANISMS OF CARBAPENEM RESISTANCE
ance mechanisms [10] are critical to reduce the risk of mor-
Enzymatic Hydrolysis
tality, length of hospitalization, and associated costs [2]. The
One key mechanism of carbapenem resistance is hydrolysis
alarming level of carbapenem resistance has presented partic-
of carbapenems by carbapenemase enzymes, which are en-
ular challenges for the management of a variety of infections
coded mainly on plasmids and are highly transmissible [16].
 
The Ambler classification system categorizes β-lactamase
Correspondence: P.  Nordmann, Medical and Molecular Microbiology, Department of enzymes into 4 groups (ie, A, B, C, D) based on their cen-
Medicine, Faculty of Science and Medicine, University of Fribourg, Chemin du Musée 18,
Fribourg CH-1700, Switzerland ([email protected]). tral catalytic domain and substrate preference (Figure 1)
Clinical Infectious Diseases®  2019;69(S7):S521–8 [17]. Of these, classes A, B, and D include carbapenemases,
© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases whereas class C enzymes hydrolyze primarily cephalosporins
Society of America. This is an Open Access article distributed under the terms of the Creative
Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ [18]. Enzymes in classes A, C, and D have serine in the ac-
by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any tive catalytic site, whereas class B enzymes are metallo-β-
medium, provided the original work is not altered or transformed in any way, and that the work
is properly cited. For commercial re-use, please contact [email protected]
lactamases (MBLs) with zinc in the active site [18]. Among
DOI: 10.1093/cid/ciz824 the newer agents, avibactam inhibits class A  (eg, Klebsiella

Epidemiology and Diagnostics of Carbapenem Resistance in GNB  •  cid 2019:69 (Suppl 7) • S521

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Figure 1.  Classification of carbapenemases/β-lactamases depending on their central catalytic domain. Adapted from [17]. Abbreviations: ACT, AmpC type β-lactamase;
AmpC, ampicillin chromosomal cephalosporinase; CMY, cephamycin-hydrolyzing β-lactamase; CTX-M, cefotaxime-hydrolyzing β-lactamase–Munich; FOX, plasmid-mediated
class  C β-lactamase; GES, Guiana extended-spectrum β-lactamase; IMI, imipenem-hydrolyzing β-lactamase; IMP, imipenemase metallo-β-lactamase; KPC, Klebsiella
pneumoniae carbapenemase; NDM, New Delhi metallo-β-lactamase; OXA, oxacillin carbapenemase/oxacillinase; SHV, sulfhydryl variant of the TEM enzyme; SME, Serratia
marcescens enzyme; TEM, Temoneira class A extended-spectrum β-lactamase; VIM, Verona integron-encoded metallo-β-lactamase.

pneumoniae carbapenemase [KPC]), class  C (eg, ampicillin Other Carbapenem Resistance Mechanisms
chromosomal cephalosporinase [AmpC]), and only some Nonenzymatic carbapenem resistance mechanisms include
class D (eg, oxacillin carbapenemase/oxacillinase [OXA]–48) loss of expression of porin-encoding genes, mutations in
serine-β-lactamases, but does not significantly inhibit the ac- chromosomally encoded porin genes (such as OprD), and
tivity of class B MBLs (eg, imipenemase metallo-β-lactamase overexpression of genes encoding efflux pumps (such as
[IMP], Verona integron-encoded metallo-β-lactamase [VIM], MexAB-OprM, MexXY-OprM, or MexCD-OprJ), particu-
New Delhi metallo-β-lactamase [NDM]) [19]. Similarly, larly in P. aeruginosa [25, 29, 30]. Porins are nonspecific chan-
vaborbactam inhibits class A and C enzymes but not those be- nels in the outer membrane of gram-negative bacteria that
longing to class B and D [20]. permit the passive transport of hydrophilic small molecules
Although most class A  enzymes do not exhibit in- and nutrients (and also some antibiotics) across the other-
trinsic carbapenemase activity, this group of enzymes in- wise impermeable membrane [30]. Porin loss and efflux pump
cludes the prevalent KPC [18]. All (class B) MBLs possess overexpression associated with carbapenem resistance may
carbapenemase activity, and this group includes the ac- also contribute to cross-resistance to other β-lactams and other
quired VIM, IMP, and NDM enzymes that may be found in antibiotic classes [31]. This is commonly observed in associa-
many gram-negative species [18]. Class  C includes AmpC tion with carbapenemase production in A.  baumannii. Some
β-lactamase enzymes that are not carbapenemases per se, Enterobacteriaceae, such as Proteus species, Providencia spe-
as their hydrolytic activity against carbapenems is very cies, and M.  morganii, have intrinsic resistance to imipenem
weak or nonexistent, but that can play a role in resistance and require resistance to other carbapenems to be classified
to carbapenems in the context of permeability defects [21]. as CRE [23]. Carbapenem resistance can also be attributed to
This is true, in particular, for many enterobacterial species mutations or other modifications that alter the production level
that naturally produce a class  C cephalosporinase (such or the binding affinity of penicillin-binding proteins, mech-
as Enterobacter species, Serratia marcescens, Proteus spe- anisms that have been observed rarely in Escherichia coli [32],
cies, Providencia species, Morganella morganii, and Hafnia P. aeruginosa [31], and A. baumannii [33].
alvei) and P.  aeruginosa [22, 23]. Class D (also termed ox-
DIAGNOSTICS
acillin carbapenemase [OXA enzymes]) enzymes consti-
tute a heterogeneous group of β-lactamases with significant Both the Clinical and Laboratory Standards Institute (CLSI)
carbapenemase activity, especially OXA-48–type enzymes in and the European Committee on Antimicrobial Susceptibility
Enterobacteriaceae and OXA-23 [24, 25], frequently found Testing (EUCAST) annually define the susceptibility break-
in A. baumannii [26, 27]. Stenotrophomonas maltophilia has points to commercially available carbapenems, including
intrinsic carbapenem resistance due to the presence of a doripenem, ertapenem, imipenem, and meropenem for
chromosomally encoded MBL, namely L1 [28]. gram-negative species, although EUCAST no longer provides

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doripenem breakpoints [34, 35]. When a strain is found to be the detection of a much higher number of target genes than
nonsusceptible to carbapenems (ie, intermediate or resistant), PCR with 100% sensitivity and typically include bacterial iden-
the mechanism of resistance is still unknown [13, 36, 37]. Thus, tification targets as well as resistance markers (eg, KPC, NDM,
to confirm the production of carbapenemases and/or presence OXA, VIM, IMP, Guiana extended-spectrum β-lactamase
of other mechanisms, further biochemical assays and/or gene- [GES], German imipenemase [GIM], and São Paulo metallo-
based tests must be performed [13, 16, 22, 23]. Determining the β-lactamase [SPM] carbapenemases). Currently available sys-
mechanism of carbapenem resistance can help in the selection tems include Verigene (Luminex, Austin, Texas) [45], BioFire
of the most appropriate antibiotic therapy early in the treatment FilmArray (Salt Lake City, Utah) [46], and the Check-Points
of gram-negative infections. For therapeutic decision making, systems [47]. Whole genome sequencing allows detection of
the rapid turnaround time (defined as 1 day or as short as <2 either carbapenemase genes or other resistance-associated mu-
hours) would be particularly beneficial in reducing length of tations and may also play a role as the technology becomes
hospitalization and/or time spent in the intensive care unit less expensive and more widespread [38]. However, such an

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[13, 37, 38]. Both biochemical and molecular technologies are approach requires a significant expertise and adequate equip-
widely available, with endorsement from CLSI, EUCAST, and/ ment, which is not systematically available, and a precise know-
or the US Food and Drug Administration. ledge of combined resistance mechanisms (eg, mutations, level
The biochemical assays include the Carba NP [37, 39], its de- of expression).
rivative Blue Carba [40], and β Carba [22] tests, which are inex- Some of these rapid gene-based assays, such as the Xpert
pensive and confirm phenotypically carbapenemase-producing Carba-R platform or BioFire FilmArray, have the potential for
organisms (but not other resistance mechanisms). These direct specimen sampling (eg, nasal swab, rectal swab, sputum,
methods are based on the expression of any carbapenemase en- wound specimen, blood, urine) without the need for culturing,
zyme during bacterial growth in culture (ie, up to 24–48 hours), allowing appropriate treatment to be initiated as soon as the
and use imipenem or meropenem as a substrate, which is then carbapenemase resistance mechanism has been identified and
hydrolyzed by the carbapenemase. The colorimetric positive minimizing the risk of treatment failure associated with empiric
signal may be obtained in <1 hour (eg, Carba NP) and can be antimicrobial therapy [10, 44].
used directly from clinical samples (blood cultures, infected Despite the technological advances in molecular and bio-
urine). Furthermore, specific inhibitors of carbapenemase ac- chemical rapid diagnostics, there are 2 fundamental consid-
tivity can be included, such as avibactam, vaborbactam, or erations: (1) a negative test does not imply that the organism
ethylenediaminetetraacetic acid [22, 38, 41]. Further biochem- is carbapenem susceptible, as it may still be resistant due to
ical assays include the carbapenemase inactivation method, nonenzymatic mechanisms; (2) conversely, the presence of a
which is also inexpensive, and the matrix-assisted laser desorp- gene does not systematically imply the organism is carbapenem
tion/ionization–time of flight mass spectrometry (MALDI- resistant, owing to the level of expression of the resistance gene;
TOF) technology, which may be cost-effective in large centers and (3) a positive biochemical test will not identify the specific
and hospitals. However, all of these methods described above, carbapenemase enzyme. Consequently, only phenotypic tests
besides having some specificity or sensitivity issues, are also un- relying on actual growth inhibition provide a full susceptibility
able to identify the exact carbapenemase enzyme and require picture.
growth of bacteria [13, 38, 42].
The specific assays used to detect the presence of known GLOBAL EPIDEMIOLOGY OF CARBAPENEM-
RESISTANT PATHOGENS
carbapenemase genes located on plasmids, or porin channel or
efflux pump mutations, are normally gene based and amplify Although data are limited for some regions, the overall burden
the potential genes present by the use of oligomer primers and of disease caused by carbapenem-resistant pathogens is similar
probes [13, 16, 38, 43]. Commercially available polymerase chain in most regions (ie, Asia-Pacific, the Indian continent, Europe,
reaction (PCR) tests include Check-Direct carbapenemase- North America, and Latin America), with nonfermenters
producing Enterobacteriaceae (CPE) assays (Check-Points, being the most problematic pathogens followed by a relatively
Wageningen, the Netherlands), Xpert Carba-R (Cepheid, lower proportion of CREs (Table 1) [3, 5, 21, 26, 41, 48–54].
Sunnyvale, California), EazyPlex SuperBug ID complete A/B Data of both large surveillance studies and smaller hospital
(Amplex, Giessen, Germany), and the very recent point-of-care investigations demonstrate similarity in carbapenem resist-
GenePOC technology (GenePOC, Quebec City, Canada). All ance rates irrespective of the methodology used to detect the
4 methods can detect KPC, NDM, and VIM encoding genes mechanism of resistance or the antibiotic used. The reported
with 100% sensitivity, and OXA-48–type carbapenemases (in- rates of carbapenem resistance seem to be considerably higher
cluding OXA-181) with 83%–100% sensitivity; however, only for nonfermenters (frequently >60%) than for fermenters (fre-
Xpert Carba-R detects IMP-1 [44]. Turnaround time is usually quently <10%) across regions [3, 21, 26, 41, 48–57]. Specifically,
the same day [13, 38]. The commercial microarrays allow for in the US based study from the Premier Healthcare Database,

Epidemiology and Diagnostics of Carbapenem Resistance in GNB  •  cid 2019:69 (Suppl 7) • S523

Table 1.  Reported Carbapenem Nonsusceptibility or Resistance Rates by Region

Nonsusceptibility or Resistance Rate

India, Nepal, Pakistan, North Latin

Species Asia-Pacific Ref. Vietnam Ref. Europe Ref. America Ref. America Ref.
a d a a
Acinetobacter 55.7%–56.2% [53] 0%–100% [26] 58.1%–60.5% [53] 32.0%–36.5% [53] 53.1%–54.6% [53]a
baumannii
78.4%–79.00% [53]a … … 76.3%–77.8% [53]a 42.3%–45.1% [53]a 85.6%–86.3% [53]a
c b c
71.4%–71.9% [49] … … 2.5%–81.5% [41] 40.1%–50.4% [3] 57.5% [51]c
b c c
25.0%–90.5% [48] … … 65.8%–84.6% [21] 11.4% [55] 21%–90% [52]d
c
… … … … 90.7%–100% [54] … … 79.3%–89.2% [56]a
b b c
Pseudomonas 17%–50% [50] … … 0%–35.6% [41] 10.3%–19.4% [3] 64.6% [51]c
aeruginosa

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25.4%–34.6% [49]c … … 24.2%–56.4% [21]c 58.5% [55]c 14%–57% [52]d
10.3%–46.7% [48]b … … 14.4% [57]a 26.1% [57]a 38.1%–45.8% [56]a
16.8% [57]a … … … … … … 24.8% [57]a
b d b c
Klebsiella 5%–25% [50] 0%–52% [26] 0.2%–33.4% [41] 3.1%–4.9% [3] 1.3%–28.6% [56]a
pneumoniae
1.6%–19.1% [49]c … … 31.7%–58.6% [21]c 12.9% [55]c 16.0% [57]a
a a a
3.8% [57] … … 15.7% [57] 6.0% [57] … …
Escherichia coli 0%–3% [50]b 0%–34% [26]d 0%–7.0% [41]b 0.2%–0.4% [3]c 0.4%–9.0% [56]a
1.6%–7.1% [49]c … … … … 4.3% [55]c … …
b d
Enterobacteriaceae 0% [50] 2.7%–21.3% [26] … … 2.10% [55]c … …
(other)
2.4%–32.1% [49]c … … … … … … … …
0.4%–12.5% [48]b … … … … … … … …
Source: [3, 21, 26, 41, 48–57].
a
Global surveillance study.
b
International (regional) surveillance study.
c
Multicenter or hospital-based study in a country.
d
Review of reported data.

which collects data on both hospital- and community-acquired K.  pneumoniae, 17.9% and 12.3% for P.  aeruginosa, and 3.1%
infections, 44.8% of A. baumannii and 14.2% of P. aeruginosa and 1.9% for Acinetobacter species, respectively [59].
isolates were carbapenem resistant, compared with only 1% Information provided by such epidemiological databases
of Enterobacteriaceae [3, 58]. Of note, this was applicable must be viewed with caution because the sites and the sample
in all infection types investigated (ie, bloodstream, respi- collection methodology may vary [41]; in addition, resistance or
ratory, urinary, and other) (Figure 2) [3, 58]. Importantly, nonsusceptibility rates may depend on the antibiotic tested [49].
82.3% of all carbapenem-resistant infections were caused by The ongoing European multicenter COMBACTE surveillance
A. baumannii or P. aeruginosa, whereas only 17.7% were caused program is a comprehensive program that collects informa-
by K.  pneumoniae or E.  coli [3, 58]. Carbapenem resistance tion on the methodology used to detect carbapenem resistance
rates by pathogen differ depending on the site of infection [3]. mechanisms in multiple gram-negative pathogens as well as re-
For example, rates for both P. aeruginosa and A. baumannii are sistance rates, which are determined by both CLSI and EUCAST
much lower in bloodstream infections (BSIs) than respiratory breakpoints [41]. Results of the COMBACTE study may clarify
infections [3]. The implication of this finding is that epidemio- the most optimal methodology for detection of carbapenem re-
logical studies that track only BSI isolates probably underreport sistance and the timings for interventions, both of which will aid
carbapenem resistance rates. Additionally, S. maltophilia, which physicians in the management of resistant infections [41].
is intrinsically carbapenem resistant, was isolated at the highest
rate from hospitalized patients with nosocomial pneumonia in GEOGRAPHIC DISTRIBUTION OF CARBAPENEM
Asia-Pacific, Europe, and North America (range, 51.7%–62.6%) RESISTANCE MECHANISMS
or BSIs in Latin America (56.8%) in the SENTRY surveillance Asia-Pacific
program between 1997 and 2016 [53]. The Japan Nosocomial In contrast to North America and Europe, NDM and other
Infections Surveillance (JANIS) 2016 report, which included MBLs (eg, IMP, VIM), and OXA-48–type, rather than KPC,
data from 1653 facilities, found that the rates of imipenem were the predominant carbapenemases in CRE in Southeast Asia
and meropenem nonsusceptibility according to CLSI 2012 [60]. A 2013–2016 study of 130 carbapenem-resistant isolates in
breakpoints were 0.1% and 0.2% for E. coli, 0.2% and 0.5% for the Philippines identified 45 (35%) carbapenemase-producing

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Figure 2.  Number of infections caused by carbapenem-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli based
on the Premier Healthcare Database. Adapted from [3]. Abbreviation: CR, carbapenem resistant.

bacterial isolates with 43 (33%) testing positive for NDM to possess a carbapenemase gene, with those encoding KPC
and 2 (1.5%) for VIM, both of which were P. aeruginosa [61]. (42%) and OXA-48 (38%) carbapenemases being found most
Surveillance reports in India and surrounding countries reveal frequently [62]. However, 29.3% (353/1203) of K. pneumoniae
that the most frequent carbapenemase enzymes remain NDM and 60.3% (117/194) of E. coli isolates were confirmed to also
in Enterobacteriaceae and OXA-23 in A. baumannii [26]. have other resistance mechanisms (Figure 3), suggesting that
a large proportion of CRE infections currently lack effective
Europe and relatively safe antibiotic treatment options [62]. Although
In the prospective, multinational European Survey on the EuSCAPE study focused on CRE infections and did not
Carbapenemase-Producing Enterobacteriaceae (EuSCAPE) collect information on nonfermenters, carbapenem-resistant
study, 37% of carbapenem-nonsusceptible K. pneumoniae and nonfermenters have been reported in some countries (eg,
19% of carbapenem-nonsusceptible E.  coli were confirmed Germany: outbreak by GIM-1 MBL-producing P.  aeruginosa;

Figure 3.  Distribution of carbapenem resistance mechanisms in Enterobacteriaceae species in the European Survey on Carbapenemase-Producing Enterobacteriaceae
(EuSCAPE) study. Adapted from [62]. Abbreviations: AmpC, ampicillin chromosomal cephalosporinase β-lactamase; CR, carbapenem resistant; KPC, Klebsiella pneumoniae
carbapenemase; NDM, New Delhi metallo-β-lactamase; OXA, oxacillin carbapenemase/oxacillinase; VIM, Verona integron-encoded metallo-β-lactamase.

Epidemiology and Diagnostics of Carbapenem Resistance in GNB  •  cid 2019:69 (Suppl 7) • S525

Greece: emergence of P.  aeruginosa concurrently producing the most common carbapenemase enzymes corresponded to
VIM and KPC) [63, 64]. OXA enzymes in this region [27], including OXA-23, OXA-58,
OXA-72, OXA-143, and OXA-253; however, NDM-1, VIM-1,
North America IMP-1, and IMP-10 have also been detected. These epidemio-
Based on North American datasets, approximately 50% of all logical studies are crucial in understanding the evolution and
CRE isolates tested appear to be CPE. In the US Centers for spread of these strains, and also highlight that molecular charac-
Disease Control and Prevention’s Multisite Gram-Negative terization of the clones spreading across hospitals may support
Surveillance Initiative, a population-based surveillance system infection control as well as physicians’ decisions with regard
from 7 US communities, 47.9% (range, 15.4%–76.5%) of CRE to selection of the best available antibiotic therapy. The broad
isolates were confirmed as CPE (all KPC) by PCR [65]. Other range of mechanisms (Figure 4) in both Enterobacteriaceae
carbapenemases (NDM, VIM, and OXA-48) are also being and nonfermenters has an impact on the selection of the most
detected in the United States [23]. Among CRE strains in the appropriate antibiotic for carbapenem-resistant infections be-

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Canadian Nosocomial Infection Surveillance Program, the cause their spectrum of activity greatly depends on the presence
most common carbapenemases were KPC-type (66.9% per of these resistance mechanisms. For example, some of the new
year) and NDM-1 (17.3% per year), with a significant increase β-lactam–β-lactamase inhibitor combination antibiotics have
in S.  marcescens enzyme family carbapenemase and OXA-48 limited activity against MBLs and nonfermenting pathogens, as
over the 5-year period [66]. In Acinetobacter species, the most described in the manuscript by Lee & Doi [71].
prevalent mechanism of resistance to carbapenems is associated
with specific carbapenemases such as OXA-23 and other OXA-
CONCLUSIONS
type carbapenemases (eg, OXA-40, OXA-58) [67].
Carbapenem resistance affects both nonfermenters and fer-
Latin America menters in all regions, and mechanisms appear to vary geo-
Investigations into specific mechanisms have revealed the graphically. However, the rates of carbapenem resistance were
spread of virtually all resistance mechanisms across the region. consistently higher in nonfermenters than fermenters. The
The first case of IMP-1–expressing K. pneumoniae was reported complexity of the overall problem is reflected by the use of
in Brazil in 2005 [68]. In a Mexican hospital, a significant in- different carbapenems in hospitals, differences in suscepti-
crease in carbapenem resistance was found between 2011 and bility breakpoints, inadequate level of infection control, and
2015, and 96% of carbapenem-resistant K.  pneumoniae ex- low availability of rapid diagnostic methods to facilitate early
pressed KPC [69]. In a study by López-García, detection of appropriate interventions in patients who are either colonized
IMP and GES enzymes was reported in carbapenem-resistant or infected by carbapenem-resistant pathogens. Overall, we
P. aeruginosa; however, some of the strains had multiple mech- observe a growing spread of carbapenemase producers (OXA-
anisms present simultaneously, such as MBLs and loss of porin 23) in A. baumannii, mostly in patients hospitalized in the in-
expression, resulting in extremely high meropenem minimum tensive care unit. Carbapenemase types in Enterobacteriaceae
inhibitory concentrations [70]. Among A.  baumannii strains, are more variable, with a trend toward dissemination of

Figure 4.  Algorithm to assess potential carbapenem resistance mechanisms in Enterobacteriaceae and nonfermenter species. Abbreviations: CPE, carbapenemase-
producing Enterobacteriaceae; CPO, carbapenemase-producing organism; CR, carbapenem resistant; CRE, carbapenem-resistant Enterobacteriaceae; IMP, imipenemase
metallo-β-lactamase; KPC, Klebsiella pneumoniae carbapenemase; L1, a class B metallo-β-lactamase; MBL, metallo-β-lactamase; NDM, New Delhi metallo-β-lactamase;
OXA, oxacillin carbapenemase/oxacillinase; VIM, Verona integron-encoded metallo-β-lactamase.

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results which can be properly interpreted for the detection of 16 April 2019; Poster 1855.

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Supplement sponsorship. This supplement is sponsored by Shionogi &
Enterobacteriaceae. Antimicrob Agents Chemother 2017; 61:e01443–17.
Co., Ltd. 21. Meletis G. Carbapenem resistance: overview of the problem and future perspec-
Potential conflicts of interest. P. N. and L. P. have codeveloped the Rapid tives. Ther Adv Infect Dis 2016; 3:15–21.
Carba NP test marketed by bioMérieux Ltd (Marcy-l’Etoile, France), under 22. European Committee on Antimicrobial Susceptibility Testing. EUCAST guide-
the trade name Rapidec Carba NP. P.  N.  has received speaker’s fees from lines for detection of resistance mechanisms and specific resistances of clinical
Shionogi. Both authors have submitted the ICMJE Form for Disclosure of and/or epidemiological importance. Version 2.0. 2017. Available at: http://www.
Potential Conflicts of Interest. Conflicts that the editors consider relevant to eucast.org/resistance_mechanisms/. Accessed 1 February 2019.
the content of the manuscript have been disclosed. 23. Centers for Disease Control and Prevention. Facility guidance for control of
carbapenem-resistant Enterobacteriaceae—November 2015 update. Available at:
https://www.cdc.gov/hai/pdfs/cre/CRE-guidance-508.pdf. Accessed 1 February 2019.
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