Carbapenemases

DisclosuresAll topics are updated as new

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 

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AuthorsJohn Quale, MDDenis Spelman, MBBS, FRACP, FRCPA, MPH

Section EditorDavid C Hooper, MDDeputy EditorElinor L Baron, MD, DTMH

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

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

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

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

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 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).

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.)

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 18.0GRAPHICSComparison 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 NDMβ-lactamase type Serine Metallo-β-lactamaseAmbler cass A BMost commonly affected species K. pneumoniae K. pneumoniae

Other species commonly affected E. coli, E. cloacae E. coli, E. cloacae

Common MLST types ST258 VariableGeographic 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 EDTAEDTA: 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-27OXA-49

2 OXA-24/OXA-40OXA-25OXA-26OXA-72

3 OXA-51 OXA-64 through OXA-71

OXA-75 through OXA-78OXA-83OXA-84OXA-86 through OXA-89OXA-91OXA-92OXA-94OXA-95

4 OXA-58 OXA-96OXA-97

5 OXA-48 

OXA-162OXA-163OXA-181OXA-204OXA-232 

Reproduced with permission from: Queenan AM, Bush K. Carbapenemases: the versatile beta-lactamases. Clin Microbiol Rev 2007; 20:440. Copyright ©2007 American Society for Microbiology.

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