This document discusses carbapenemases, which are carbapenem-hydrolyzing beta-lactamases that confer resistance to carbapenems. Carbapenemases are classified based on their molecular structure into class A, B, C, and D beta-lactamases. The most clinically important carbapenemases are KPC (Klebsiella pneumoniae carbapenemase) and NDM-1 (New Delhi metallo-beta-lactamase). These enzymes can spread between bacteria on mobile genetic elements and pose a challenge for treatment. Detection of carbapenemase-producing organisms can be difficult as some have carbapenem minimum inhibitory concentrations just below standard breakpoints.

1. Carbapenemases
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evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2013. | This topic last updated: Μαρ 5, 2013.
INTRODUCTION — Carbapenem antibiotics have an important antibiotic niche in that they retain
activity against the chromosomal cephalosporinases and extended-spectrum beta-lactamases found
in many gram-negative pathogens [1,2]. The emergence of carbapenem-hydrolyzing beta-
lactamases has threatened the clinical utility of this antibiotic class and brings us a step closer to the
challenge of "extreme drug resistance" in gram-negative bacilli [3].
Issues related to carbapenemases will be reviewed here. Penicillinases and cephalosporinases are
discussed in detail separately. (See "Extended-spectrum beta-lactamases".)
CLASSIFICATION — Carbapenemases are carbapenem-hydrolyzing beta-lactamases that confer resistance
to a broad spectrum of beta-lactam substrates, including carbapenems. This mechanism is distinct from
other mechanisms of carbapenem resistance such as impaired permeability due to porin mutations, although
the susceptibility patterns for isolates with a carbapenemase and those with porin mutations can be identical.
The carbapenemases have been organized based on amino acid homology in the Ambler molecular
classification system. Class A, C, and D beta-lactamases all share a serine residue in the active site, while
Class B enzymes require the presence of zinc for activity (and hence are referred to as metallo-beta-
lactamases). Classes A, B, and D are of greatest clinical importance among nosocomial pathogens.
Class A beta-lactamases — Class A beta-lactamases are characterized by their hydrolytic mechanisms that
require an active-site serine at position 70 [4]. These include penicillinases and cephalosporinases in the
TEM, SHV, and CTX-M-type groups (which do not hydrolyze carbapenems), as well as additional groups that
possess beta-lactamase (including carbapenemase) activity [1,5]. (See "Extended-spectrum beta-
lactamases".)
Class A beta-lactamases with carbapenemase activity may be encoded on chromosomes or plasmids.
Chromosomally-encoded enzymes include SME (Serratia marcescens enzyme), NMC (non-metalloenzyme
carbapenemase) and IMI (imipenem-hydrolyzing) beta-lactamases. SME have been recovered in a small
number of S. marcescens isolates, while IMI and NMC have been identified among Enterobacter isolates [6-
8]. Plasmid-encoded enzymes include KPC (Klebsiella pneumoniae carbapenemase) and GES (Guiana
extended spectrum). GES has been described in P. aeruginosa and K. pneumoniae [5,9-11]. (See 'Klebsiella
pneumoniae carbapenemase (KPC)' below.)
Klebsiella pneumoniae carbapenemase (KPC) — The most clinically important of the Class A
carbapenemases is the Klebsiella pneumoniae carbapenemase (KPC) group (table 1). These enzymes
reside on transmissible plasmids and confer resistance to all beta-lactams [9]. Several different variants
of KPC enzymes have been identified. Some of the variants hydrolyze beta-lactams at varying rates,
which may contribute to different susceptibility profiles in KPC-producing bacteria when tested in vitro
[12,13].
KPC can be transmitted from Klebsiella to other genera, including E. coli, Pseudomonas aeruginosa,
Citrobacter, Salmonella, Serratia, and Enterobacter spp. [14-19].
Official reprint from UpToDate® www.uptodate.com
©2013 UpToDate®
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Authors
John Quale, MD
Denis Spelman, MBBS, FRACP, FRCPA, MPH
Section Editor
David C Hooper, MD
Deputy Editor
Elinor L Baron, MD, DTMH

2. Class B beta-lactamases — Class B beta-lactamases are also known as the metallo-beta-lactamases
(MBLs), which are named for their dependence upon zinc for efficient hydrolysis of beta-lactams. As a result,
MBLs can be inhibited by EDTA (an ion chelator), although they cannot be inhibited by beta-lactamase
inhibitors such as tazobactam, clavulanate, and sulbactam. The first MBL, IMP-1, was described in Japan in
1991 [20]. Subsequently, additional groups of acquired MBLs have been identified: IMP, VIM, GIM, SPM, and
SIM. There are a number of variants within each MBL group (for example, there are 19 IMP variants within
the IMP group) [21,22].
There are both naturally occurring and acquired MBLs. Naturally occurring MBLs are chromosomally
encoded and have been described in Aeromonas hydrophilia, Chryseobacterium spp., and
Stenotrophomonas maltophilia [21]. Acquired MBLs consist of genes encoded on integrons residing on large
plasmids that are transferable between both species and genera [4,23-28]. In a hospital outbreak involving
62 patients (including 40 intensive care unit patients), for example, an MBL gene (bla IMP-4) spread among
seven different gram-negative genera (Serratia, Klebsiella, Pseudomonas, Escherichia, Acinetobacter,
Citrobacter, and Enterobacter) [23,29].
New Delhi metallo-beta-lactamase (NDM-1) — Enterobacteriaceae isolates carrying a novel MBL gene,
the New Delhi metallo-beta-lactamase (NDM-1), were first described in December 2009 in a Swedish
patient hospitalized in India with an infection due to Klebsiella pneumoniae (table 1) [30].
The gene encoding this MBL is located in a very mobile genetic element, and the pattern of spread appears
to be more complex and more unpredictable than that of the gene encoding KPC [30,31]. Furthermore, the
large number of resistance determinants in the isolates studied raise concern that this gene is an important
emerging resistance trait [32]. In general, bacteria containing NDM-1 have tested susceptible
to colistin or tigecycline, though such susceptibility may be short-lived.
In addition to K. pneumoniae, NDM-1 has also been identified in other Enterobacteriaceae (including E. coli
and Enterobacter cloacae) [33] as well as non-Enterobacteriaceae (including Acinetobacter) [34].
Class D beta-lactamases — Class D beta-lactamases are also referred to as OXA-type enzymes because
of their preferential ability to hydrolyze oxacillin (rather than penicillin) [35]. Enzymes in this group are
variably affected by the beta-lactamase inhibitors clavulanate, sulbactam, or tazobactam. OXA
carbapenemases have been identified in Acinetobacter baumannii [35-44] and Enterobacteriaceae
(especially K. pneumoniae, E. coli, and E. cloacae) [45].
Among the heterogeneous OXA group (which includes more than 100 enzymes), five subfamilies have been
identified with varying degrees of carbapenem-hydrolyzing activity: OXA-23, OXA-24/OXA40, OXA-48, OXA-
58, and OXA-51 (table 2). The first four groups are carried on transmissible plasmids, while the last group,
OXA-51, is chromosomally encoded and intrinsic to A. baumannii species. While most isolates of A.
baumannii possessing an OXA-23, -24/40, or -58 type carbapenemase are resistant to carbapenems,
Enterobacteriaceae with OXA-48-type enzymes have variable susceptibility to these agents. Expression of a
promoter insertion element (ISAba1) in OXA-23 and OXA-51 likely contributes to carbapenem resistance
[38].
EPIDEMIOLOGY
Distribution
Klebsiella pneumoniae carbapenemases — The Klebsiella pneumoniae carbapenemase (KPC) (table
1) was first described in a clinical isolate of K. pneumoniae in the late 1990s in North Carolina [9,46].
Shortly thereafter, several reports described hospital outbreaks in the northeastern United States
involving K. pneumoniae carrying KPC-2, an enzyme later found to be identical to the initially described
KPC [47-50]. Subsequently, an outbreak involving K. pneumoniae with KPC-3 (which differs from KPC-
1/KPC-2 by a single amino acid) was described in New York City [51]. There has been progressive
spread of KPC in the United States, where, as of 2010, KPC-production has been identified in isolates

3. from 36 states [52,53]. It is the most common carbapenemase in the United States.
KPC-possessing isolates have also been increasingly recovered from other regions of the world, including
Europe [54,55], Asia [14,56,57], and South America [15,58].
Metallo-beta-lactamases — Metallo-beta-lactamases (MBLs) were initially described in Japan in 1991
[20]. MBLs have since been described in Korea, Singapore, Taiwan, Hong Kong, China, Malaysia, Brazil,
England, Italy, Canada, United States, Australia, and Colombia [21,59-62]. The transfer of patients
between hospitals and the increase in international travel may be important factors in the geographical
dissemination of MBL genes [21,27,59,63,64].
The MBL gene, the New Delhi metallo-beta-lactamase (NDM-1) (table 1), was first described in December
2009 in a K. pneumoniae isolate from a Swedish patient who had been hospitalized in India [30]. Subsequent
reports have included patients who have traveled and undergone procedures (so called “medical tourism”) in
India and Pakistan [33], as well as cases reported in Asia, Europe, North America, and Australia
[31,33,53,65,66].
In the United States, between January 2009 and February 2011, seven Enterobacteriaceae isolates with
NDM-1 production were reported to the Centers for Disease Control and Prevention (CDC) [53]. These were
all identified in patients who had traveled to India or Pakistan, the majority of whom received medical care
there.
Class D carbapenemases — While A. baumannii carrying OXA-23-, OXA-24/40-, and OXA-58-type
carbapenemases are especially problematic in Europe, they have also been recovered from medical
centers in Eastern Asia, the Middle East, Australia, South America, and the United States [35]. The first
isolate of K. pneumoniae with OXA-48 was identified in Turkey; since then, hospital outbreaks from that
country have been reported [67]. Enterobacteriaceae with OXA-48-type enzymes have subsequently
been recovered in Europe, the Middle East, and Northern Africa.
Risk factors — Carbapenemase-producing organisms can arise from previously carbapenemase-negative
strains by acquisition of genes from other bacteria. Use of broad spectrum
cephalosporins and/or carbapenems is an important risk factor for the development of colonization or
infection with such pathogens [29,63,68]. As an example, in one case-control study, 86 percent of patients
with a KPC-producing Enterobacteriaceae isolate (n = 91) had a history of cephalosporin use in the past
three months, compared with 69 percent of those with extended-spectrum beta-lactamase-producing isolates
and 27 percent of those with fully susceptible isolates [69].
Although a risk factor, prior receipt of carbapenems is not essential for acquisition of these strains. Reported
carbapenem use among patients prior to the isolation of MBL, for example, varies from 15 to 75 percent
[56,57].
Additional risk factors that have been associated with infection or colonization with a carbapenemase-
producing organism include the following [16,18,23,47,57,58,70-72]:
• trauma
• diabetes
• malignancy
• organ transplantation
• mechanical ventilation
• indwelling urinary or venous catheters
• overall poor functional status or severe illness
Clinicians should be also aware of the possibility of NDM-1-producing Enterobacteriaceae in patients who

4. have received medical care in India and Pakistan [31]. (See 'Metallo-beta-lactamases' above.)
Transmission — Many carbapenemases reside on mobile genetic elements, such as transposons or
plasmids, and have the potential for widespread transmission to other isolates and genera of bacteria.
Furthermore, Enterobacteriaceae, which may harbor carbapenemase-encoding genes, can spread from
person to person.
One particular clone of K. pneumoniae that carries the KPC gene has been reported as the predominant
isolate across several geographic areas, suggesting cross-infection within and outside of healthcare systems
[67].
Limited data using DNA fingerprinting and pulse-field gel electrophoresis also suggest cross-transmission of
bacteria with MBLs within hospitals [28]. This was illustrated in a study of 66 MBL-positive isolates from 54
hospitalized patients in a hospital outbreak [60]. Environmental screening isolated MBL-producing organisms
from sinks and stethoscopes, suggesting these as possible environmental reservoirs; interestingly, there
were no positive cultures from the hands of the 10 healthcare workers screened. The outbreak was curtailed
following intensive environmental cleaning with hypochlorite, replacement of poorly designed sinks, and
disassembling and cleaning of stethoscopes. In another outbreak, environmental screening demonstrated a
single positive swab from a ventilator; all other environmental swabs of hands, gowns, medical fluids, air and
water samples, and endoscopes were negative [72].
NDM-1-positive bacteria have been identified in public water supplies in India, highlighting the potential for
environmental dissemination, and the importance of environmental surveillance [73]. In addition, two isolates
of Pseudomonas aeruginosa containing an MBL gene (bla VIM) have been also detected from aquatic
sources (one isolate from a river and the second from sewage), raising the possibility of aquatic reservoirs
for these organisms [74].
Patients themselves may also serve as an important reservoir for resistant Enterobacteriaceae, as intestinal
colonization with carbapenemase-producing organisms has been reported [21,28,75,76].
DETECTION
Clinical laboratory testing — Most K. pneumoniae and E. coli without carbapenemases have minimum
inhibitory concentrations (MICs) to imipenem and meropenem that are ≤0.5 mcg/mL. Thus, the identification
of E. coli or K. pneumoniae with overt resistance to any of the carbapenems should raise suspicion that it
may be harboring a carbapenemase enzyme. Certain susceptibility patterns in other Enterobacteriaceae may
be suggestive of the presence of a carbapenemase. As an example, recovery of an isolate that is susceptible
to third generation cephalosporins but resistant to imipenem should raise the possibility of an underlying
Serratia marcescens enzyme (SMC) in Serratia species and a non-metalloenzyme carbapenemase (NMC)
or imipenem-hydrolyzing beta-lactamase (IMI) in Enterobacter species [6-8].
Detection of carbapenemase-producing Enterobacteriaceae can be problematic. Some isolates have MICs
that fall just below the traditional breakpoints for susceptibility and therefore may not be recognized as
carbapenemase producers by the clinical laboratory [23,60,77-80]. In one report, up to 87 percent of K.
pneumoniae carbapenemase (KPC)-producing K. pneumoniae were reported to be susceptible to
carbapenems according to breakpoints typically in use prior to 2011 [81]. Detection of Enterobacteriaceae
harboring OXA-48-type enzymes can be similarly challenging [45].
In 2010, the Clinical and Laboratory Standards Institute (CLSI) updated new MIC and disk diffusion
breakpoints for the Enterobacteriaceae based on pharmacokinetic-pharmacodynamic data of recommended
dosage regimens [82-85]. The new MIC breakpoints are one to three doubling dilutions lower than the
original breakpoints, and the new disk diffusion criteria include larger zone diameters than those in previous
guidelines. Thus, many organisms that previously would have been categorized as susceptible using the
former breakpoints may now be considered intermediate or resistant. In clinical laboratories that have

5. implemented these new breakpoints, additional tests to detect extended-spectrum beta-lactamases and
carbapenemases need not be routinely performed for clinical management. However, phenotypic or
genotypic testing for carbapenemases may be useful for isolates that test in the susceptible range to
carbapenems but have reduced susceptibility. Additionally, carbapenemase testing may be performed for
infection control purposes, and isolates may be forwarded through state public health laboratories to the
United States Centers for Disease Control and Prevention (CDC) for further characterization [31].
(See 'Other phenotypic tests' below.)
P. aeruginosa and A. baumannii can become resistant to carbapenems without harboring a carbapenemase;
determining which isolates have a carbapenemase based on susceptibility profiles can be difficult. In regions
where metallo-beta-lactamases (MBL) and OXA enzymes are endemic, isolates of P. aeruginosa and A.
baumannii that are highly resistant to carbapenems, cephalosporins, and penicillins should be suspected of
carrying one of these enzymes. In addition, presence of an underlying MBL should be considered if an
isolate retains susceptibility to aztreonam [86].
Other phenotypic tests — For laboratories that have implemented the updated 2010 CLSI breakpoints for
carbapenem susceptibility, additional tests are no longer routinely recommended for detection of
carbapenemase-producing organisms. For clinical laboratories that have not yet implemented the updated
CLSI breakpoints, additional tests are often employed to improve the detection of carbapenemases.
For example, the modified Hodge test can be used to detect carbapenemase activity [87,88]. This test
involves streaking a clinical isolate near an imipenem disk that has been placed on an agar plate containing
a susceptible control organism. Growth of the control organism around the imipenem disk in the region of the
streak suggests carbapenemase activity in the clinical isolate. However, the modified Hodge test has several
drawbacks. Assessment of the test result may be difficult and subject to individual interpretation. Additionally,
it has poor sensitivity for metallo-beta-lactamase (MBL) detection, although this can be improved with the
addition of zinc [89]. False positive Hodge tests have also been reported [90].
Other methods of carbapenemase detection include rapid biochemical tests [91], mass spectrometric
detection, and microbiological methods that take advantage of particular characteristics of carbapenemases,
such as their zinc dependence [77]. The particular test employed varies widely across different laboratories.
Other tests are not always reliable for detecting MBLs in organisms with apparent carbapenem susceptibility
[21,27,92]. These include a combination disc tests using imipenem and EDTA discs or using two
carbapenem discs (including one with EDTA incorporated) [93-96] and the commercially available MBL E-
test.
Direct genotypic identification — Identification of specific carbapenemases can be accomplished utilizing
molecular techniques [23,38,79,97-99]. These include multiplex polymerase chain reaction (PCR) assays
and DNA microarrays that can screen at once for several different types of enzymes, including Klebsiella
pneumoniae carbapenemases, specific MBLs, and OXA-type carbapenemases. Detection of organisms
harboring these enzymes will be greatly improved as these technologies become incorporated into clinical
practice.
CLINICAL DISEASE — Carbapenemase-producing organisms can cause clinical infections or asymptomatic
colonization [18,56]. Blood stream infections, ventilator-associated pneumonia, urinary tract infection, and
central venous catheter infections have been described [23,28,60,95]. These organisms have been isolated
from respiratory tract specimens, abdominal swabs, catheters, abscesses, urine, and surgical wounds
[28,29,56,60,95,100,101]. Sporadic hospital-acquired infections and outbreaks due to hospital-based clonal
spread have been described in both tertiary and community hospitals [23,29,60,102].
The above clinical syndromes are discussed in more detail in the corresponding topic reviews.
TREATMENT — The optimal treatment of infection due to carbapenemase-producing organisms is
uncertain, and antibiotic options are limited. Because the presence of a KPC or metalloenzyme

6. carbapenemase confers resistance to all penicillins, cephalosporins, and carbapenems, selection of
antibiotic therapy should be tailored to antimicrobial susceptibility results for agents outside the beta-lactam
and carbapenem classes. Additional antibiotic susceptibility testing should be requested
for colistin, aztreonam, tigecycline,fosfomycin (particularly for urinary tract isolates), and rifampin [103,104].
(See 'Possible antimicrobial options' below.)
Furthermore, despite limited clinical data, for patients with severe infections (including bacteremia) due to a
carbapenemase-producing gram-negative organism, we suggest using combination antimicrobial therapy
with two or more agents because of the high associated mortality, the concern for emergence of resistance
during monotherapy, and the lack of clearly effective single drug alternatives. (See 'Combination
therapy' below.)
Management of patients with infections due to carbapenemase-producing organisms should be done in
consultation with an expert in the treatment of multi-drug resistant bacteria.
In vitro susceptibility — The reliability of carbapenem susceptibility testing to determine clinical
management depends on the breakpoints utilized by the clinical laboratory. If the 2010 Clinical and
Laboratory Standards Institute (CLSI) breakpoints are being implemented to determine carbapenem
susceptibility, carbapenemase-producing organisms generally will test intermediate or resistant, and
therefore carbapenems and beta-lactamase inhibitors should not be used alone to treat such organisms. In
contrast, organisms that test susceptible to carbapenems according to the 2010 CLSI breakpoints likely do
not produce a carbapenemase, and thus carbapenems will likely retain efficacy. However, if older
breakpoints are still being utilized, carbapenems and beta-lactamase inhibitors should not be used alone
against organisms that have phenotypic evidence of a carbapenemase (eg, positive Hodge test) or are
otherwise suspected of harboring a carbapenemase, regardless of susceptibility results [23,27]. Although
some carbapenemase-producing Enterobacteriaceae (especially K. pneumoniae) may have carbapenem
minimum inhibitory concentrations (MICs) within the susceptible range using older breakpoints, the MICs
vary with the susceptibility testing method and can rise as the inoculum increases [100]; thus, carbapenems
cannot be relied upon as single agents in such cases. (See above.)
Beta-lactamase inhibitors are ineffective against K. pneumoniae carbapenemase (KPC)-, metallo-beta-
lactamase (MBL)-, and most OXA-possessing strains; most multidrug-resistant isolates of A. baumannii have
reduced susceptibility to sulbactam [39,51,105,106].
In addition, resistance genes for other antibiotics outside the beta-lactam class, including aminoglycosides
and fluoroquinolones, are frequently present in carbapenemase-producing strains [21,28]. For KPC-carrying
K. pneumoniae, resistance rates of 98 percent have been reported for the fluoroquinolones, and
approximately 50 percent are resistant to gentamicin and amikacin [105].
Possible antimicrobial options
• Polymyxins retain activity against most multidrug-resistant gram-negative pathogens, although
clinical experience with this drug class for treatment of these organisms is limited [21,107].
Polymyxin-resistant, MBL-producing K. pneumoniae has been reported [108]. Combining polymyxin
B with other antimicrobial agents (eg, tigecycline, carbapenems or rifampin) can result in enhanced
in vitro activity, although the clinical utility of combination therapy has only been preliminarily
evaluated [109-113]. (See 'Combination therapy' below and "Colistin: An overview".)
• Aztreonam may be a useful treatment for patients whose isolates (particularly MBLs) demonstrate in
vitro susceptibility to this agent [114]. However, clinical experience with aztreonam for treatment of
serious infections due to MBL-producing bacteria is very limited. Investigation is underway to
develop specific MBL inhibitors for clinical use [115].
• Tigecycline may be an alternative agent to which carbapenemase-producing isolates demonstrate in
vitro susceptibility, although clinical experience with this agent in the setting of multidrug-resistant

7. gram-negative pathogens is limited [47,51,56,105]. Tigecycline treatment failures have been
reported, even though pretherapy tigecycline MICs predicted clinical success [116]. In addition, the
efficacy of tigecycline in the setting of bacteremia requires further evaluation. Moreover, tigecycline
has been associated with an increased risk of all-cause mortality compared with other agents, most
clearly among patients with hospital-acquired pneumonia [117,118]. (See "Antibiotic studies for the
treatment of community-acquired pneumonia in adults", section on 'Tigecycline versus other drugs'.)
• Fosfomycin is an oral antimicrobial agent primarily used to treat urinary tract infections. In one study
of a panel of 81 carbapenem-resistant Enterobacteriaceae of various types and species, 60 percent
tested susceptible to this agent [104]. In a small prospective study of 11 patients, an intravenous
preparation of fosfomycin was used to successfully treat various carbapenem-resistant K.
pneumoniae infections [119]. Of note, intravenous fosfomycin is not available in many countries,
including the United States and Australia.
• The combination of polymyxins and rifampin appears to have synergistic activity in vitro against
carbapenemase-producing organisms [105,120]. Although some experts have used this combination
in clinical practice, there are no published clinical reports evaluating its efficacy.
Combination therapy — Outbreaks of polymyxin-resistant, carbapenemase-producing K. pneumoniae have
been reported, and emergence of polymyxin-resistant K. pneumoniae in patients receiving polymyxin
monotherapy has been documented [108,121,122]. Additionally, in an in vitro infection model, emergence of
resistant subpopulations of P. aeruginosa was observed during exposure to polymyxin at doses that
exceeded those used clinically [123]. Thus, there is considerable interest in using antibiotic regimens that
include more than one drug.
Clinical evidence suggests that treatment with combination therapy may be beneficial [124-129]. In a
retrospective study of 125 patients with bacteremia due to K. pneumoniae confirmed by polymerase chain
reaction to harbor the KPC gene, the overall mortality rate at 30 days was 42 percent [128]. The mortality
rate was lower among patients who received combination therapy with two or more drugs (27 of 79 [34
percent]) compared with monotherapy with colistin, tigecycline, or gentamicin (25 of 46 [54 percent]).
Patients treated with a combination of a polymyxin plus tigecycline had a mortality rate of 30 percent (7 of
23), while the regimen of colistin, tigecycline, and extended-infusion meropenem (a dose of 2 grams infused
over three or more hours every eight hours) was associated with the lowest mortality rate (2 of 16 [12.5
percent]). Similar findings were observed in a smaller retrospective study of 41 patients with KPC-producing
K. pneumoniae bacteremia, in which the mortality rate was 13 percent (2 of 15) with definitive combination
therapy (generally a polymyxin or tigecycline with a carbapenem) compared with 58 percent (11 of 19) with
monotherapy [124].
Based on these limited clinical data in addition to in vitro studies demonstrating synergy with combination
regimens [130], we suggest treatment with a combination of two or more agents instead of monotherapy for
patients with serious infections (including bacteremia) due to carbapenem-resistant Enterobacteriaceae. In
the few published reports, the combination of a polymyxin with tigecycline has been described the most and
is thus a reasonable first choice, assuming the isolate is susceptible to both. For patients who are critically ill
or have deep-seated infections (eg, meningitis), we often add a carbapenem as a third agent to this
combination regimen. If the isolate is resistant to the polymyxins, we generally use tigecycline with a different
second agent (most commonly a carbapenem, regardless of in vitro susceptibility testing). Conversely, if the
isolate is resistant to tigecycline, we generally use a polymyxin with a different second agent (most
commonly a carbapenem or rifampin).

8. For carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa, a polymyxin is usually
the backbone of therapy. Convincing clinical data to support combination therapy for these organisms is
lacking. However, in vitro studies have demonstrated enhanced antimicrobial activity against such strains
when a polymyxin is combined with other agents (most commonly a carbapenem or rifampin) [111,112,120].
Based on these and personal experience, we frequently use a polymyxin in addition to rifampin or a
carbapenem for patients with serious infections (including bacteremia) due to these drug-resistant
organisms.
Management of patients with infections due to carbapenemase-producing organisms should be done in
consultation with an expert in the treatment of multi-drug resistant bacteria.
INFECTION CONTROL — Hospitalized patients infected or colonized with carbapenemase-producing
bacteria should be placed on contact precautions [28,58,60,75,131]. Other standard measures, such as hand
hygiene, minimizing the use of invasive devices, and antimicrobial stewardship, are important to infection
control in general and likely to limit spread of resistant organisms.
Screening high-risk patients to detect rectal colonization has been suggested as an important infection
control modality [21,28,75,76]. Several studies have documented reduced transmission of KPC-producing
Klebsiella pneumoniae when comprehensive infection control protocols, including active surveillance, have
been enacted [132-134]. Although the impact of surveillance itself is difficult to assess, it may be useful in the
setting of outbreaks due to carbapenemase-resistant organisms, as recommended by the United
StatesCenters for Disease Control and Prevention (CDC), or among patients with recent travel to areas
where carbapenemases are more prevalent. (See "General principles of infection control".)
SUMMARY AND RECOMMENDATIONS
• The carbapenem-hydrolyzing beta-lactamase is an important emerging mechanism of antimicrobial
resistance among nosocomial gram-negative pathogens. These enzymes are classified on the basis
of their amino acid homology; Classes A, B, and D are of greatest clinical importance.
(See 'Classification' above.)
• The clinically most important of the Class A carbapenemases is the Klebsiella pneumoniae
carbapenemase (KPC) group, which has been implicated in several outbreaks (table 1). (See 'Class
A beta-lactamases' above and 'Klebsiella pneumoniae carbapenemase (KPC)' above.)
• Class B beta-lactamases are known as the metallo-beta-lactamases (MBLs), which are named for
their dependence upon zinc for efficient hydrolysis of beta-lactams. The New Delhi metallo-beta-
lactamase (NDM-1) is an important emerging carbapenemase in this group (table 1). (See 'Class B
beta-lactamases' above and 'New Delhi metallo-beta-lactamase (NDM-1)' above.)
• Class D beta-lactamases are referred to as OXA-type enzymes because of their preferential ability to
hydrolyze oxacillin (rather than penicillin). (See 'Class D beta-lactamases' above.)
• Implementation of the lower 2010 Clinical and Laboratory Standards Institute (CLSI) breakpoints for
carbapenem susceptibility improves the detection of carbapenemase-producing Enterobacteriaceae.
Identifying strains of P. aeruginosa or A. baumannii with carbapenemases can be difficult. Isolates
resistant to penicillins, cephalosporins, and carbapenems with retained susceptibility
to aztreonam should be suspected of carrying an MBL. (See 'Detection' above.)
• Use of broad spectrum cephalosporins and/or carbapenems is an important risk factor for the
development of colonization or infection with carbapenemase-producing organisms, although prior
receipt of carbapenems is not essential for acquisition of these strains. (See 'Risk factors' above.)
• Carbapenemase-producing organisms can cause clinical infections or asymptomatic colonization.
Carbapenemase-producing bacteria have been implicated in a variety of infections, including
bacteremia, ventilator-associated pneumonia, urinary tract infection, and central venous catheter
infection. (See 'Clinical disease' above.)

9. • Selection of antibiotic therapy should be tailored according to the antimicrobial susceptibility test
result. In particular, antibiotic susceptibility testing should be requested
for colistin, aztreonam, tigecycline, and fosfomycin. (See 'Treatment' above.)
• For patients with serious infections, including bacteremia, due to a carbapenemase-producing gram-
negative organism, we suggest using combination therapy with two or more antimicrobial agents
instead of monotherapy (Grade 2C). Preliminary clinical evidence suggests that treatment with a
regimen that combines a polymyxin, tigecycline, or a carbapenem (or all three) is associated with
lower mortality than single-agent regimens for infections with carbapenemase-producing
Enterobacteriaceae. (See 'Combination therapy' above.)
• Patients infected or colonized with carbapenemase-producing bacteria should be placed on contact
precautions. Screening high-risk patients to detect rectal colonization may also be helpful in
controlling transmission. (See 'Infection control' above.)
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Topic 471 Version 18.0
GRAPHICS
Comparison of the two most common causes of carbapenem resistance
in Enterobacteriaceae: Klebsiella pneumoniae carbapenemase (KPC)
and New Delhi Metallo-β-Lactamase (NDM) type β-lactamases
KPC NDM
β-lactamase type Serine Metallo-β-lactamase
Ambler cass A B
Most commonly affected
species
K. pneumoniae K. pneumoniae
Other species commonly
affected
E. coli, E. cloacae E. coli, E. cloacae
Common MLST types ST258 Variable
Geographic epicenter NE USA India, Pakistan
β-lactam antibiotics affected
Penicillins, cephalosporins,
carbapenems
Penicillins, cephalosporins,
carbapenems
Phenotypic detection
Modified Hodge Test (MHT)
positive
Unknown (positive MHT likely)
Inhibitors Boronic acid EDTA
EDTA: ethylene diaminete traacetic acid.
Reproduced from: Sidjabat H, Nimmo GR, Walsh TR, et al. Carbapenem
Resistance in Klebsiella pneumoniae Due to the New Delhi Metallo-β-
lactamase. Clin Infect Dis 2011; 52:481, by permission of Oxford University
Press. Copyright © 2011.
Carbapenemase subgroups of the OXA family of beta-lactamases
Cluster Enzyme subfamily Additional OXA member(s)
1 OXA-23 (ARI-1)
OXA-27
OXA-49
2 OXA-24/OXA-40
OXA-25
OXA-26
OXA-72
3 OXA-51
OXA-64 through OXA-71
OXA-75 through OXA-78
OXA-83
OXA-84
OXA-86 through OXA-89
OXA-91
OXA-92
OXA-94
OXA-95
4 OXA-58
OXA-96
OXA-97
5 OXA-48
OXA-162
OXA-163
OXA-181
OXA-204
OXA-232
Reproduced with permission from: Queenan AM, Bush K. Carbapenemases:

17. the versatile beta-lactamases. Clin Microbiol Rev 2007; 20:440. Copyright
©2007 American Society for Microbiology.
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