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Carbapenem-resistant E. coli, K. pneumoniae, and other Enterobacterales (CRE)

Carbapenem-resistant E. coli, K. pneumoniae, and other Enterobacterales (CRE)
Literature review current through: Jan 2024.
This topic last updated: Jul 13, 2023.

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].

This topic addresses issues related to carbapenem-resistant Enterobacterales (CRE). Enterobacterales that produce penicillinases and cephalosporinases are discussed in detail separately, as are carbapenem-resistant gram-negative bacilli that are not of the Enterobacterales order. (See "Extended-spectrum beta-lactamases" and "Acinetobacter infection: Treatment and prevention" and "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections" and "Stenotrophomonas maltophilia".)

DEFINITIONS

The Enterobacterales order — Enterobacterales is an order of bacteria that contains seven groups (ie, families) of gram-negative bacilli [4,5]. Bacteria within the Enterobacterales families include several clinically relevant bacteria that commonly cause infections.

The most clinically relevant families within the Enterobacterales order include the following:

Enterobacteriaceae family – This family includes at least 33 genera of bacteria, some of which cause human disease. The most notable are Escherichia (eg, Escherichia coli), Klebsiella, Enterobacter, Citrobacter, Salmonella, and Shigella. Other relevant genera within this family include Cronobacter, Kluyvera, Leclercia, Raoultella, and Pseudoescherichia.

Morganellacaeae family – Clinically relevant genera in this family include Proteus, Morganella, and Providencia.

Other families include genera such as Serratia, Erwinia, Hafnia, Peptobacterium, and Yersinia.

Carbapenem-resistant Enterobacterales — The United States Centers for Disease Control and Prevention (CDC) defines carbapenem-resistant Enterobacterales (CRE) as bacteria within the Enterobacterales order that are resistant to at least one carbapenem (ie, ertapenem, meropenem, doripenem, or imipenem) or that produce a carbapenemase enzyme [6].

Enterobacterales within the Morganellacaeae family (eg, Proteus spp, Morganella spp, and Providencia spp) are intrinsically resistant to imipenem, so only ertapenem, meropenem, and doripenem are used to determine if these organisms meet the CRE definition.

CRE are often divided into carbapenemase-producing isolates and noncarbapenemase-producing isolates, based on the mechanism of resistance:

Noncarbapenemase-producing CRE – Many CRE isolates do not have carbapenemase genes [6,7]. Usually, carbapenem resistance in these isolates is due to acquisition or upregulation of a beta-lactamase gene coupled with concomitant presence of a chromosomal mutation in a porin gene that limits the ability of carbapenems to enter the bacterium. The epidemiology of noncarbapenemase-producing CRE is discussed elsewhere. (See 'Overall prevalence of CRE' below.)

Carbapenemase-producing CRE – In some CRE isolates, carbapenem resistance is due to the presence of carbapenemases. Carbapenemases are enzymes produced by the bacteria that inactivate carbapenem antibiotics and typically other beta-lactam antibiotics including penicillins and cephalosporins. The epidemiology of carbapenemase-producing CRE is discussed elsewhere. (See 'Carbapenemases' below.)

EPIDEMIOLOGY

Overall prevalence of CRE — Globally, CRE rates vary widely with per-capita rates estimated to be highest in Russia, the eastern Mediterranean region, India, and Southeast Asia [8,9]. In the United States, approximately 12,000 CRE infections are estimated to occur per year in hospitalized patients; estimated deaths in the United States in 2017 were 1100, and the attributable healthcare costs were $130 million [7].

Worldwide data regarding the proportion of CRE isolates that produce carbapenemases is limited, primarily due to lack of widespread carbapenemase testing. In the United States, approximately 30 percent of all CRE isolates produce carbapenemases; the remaining 70 percent of CRE isolates are carbapenem-resistant due to other mechanisms [6,9]. Among United States CRE isolates resistant to every available carbapenem, up to 60 percent produce a carbapenemase [10,11].

Carbapenemases — There are many different carbapenemases, and the prevalence of each varies geographically.

Classifications and geographic distribution — The carbapenemases are organized into different classes within the Ambler molecular classification system, which is a classification system for all beta-lactamases.

Within the Ambler molecular classification system, beta-lactamases (including carbapenemases) are grouped based on their amino acid homology. 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 [MBLs]).

Beta-lactamases, including carbapenemases, are encoded from genes that reside on chromosomes or plasmids. Genes that reside on plasmids are often capable of transferring to other bacteria within the same species or to other genera, which can lead to rapidly expanding outbreaks. In contrast, genes that reside on chromosomes cannot be transferred to other bacteria, and outbreaks of isolates that harbor chromosomal genes typically occur via spread of a single bacterial clone.

Class A beta-lactamases – This class includes penicillinases and cephalosporinases in the TEM, SHV, and CTX-M-type groups (which do not inactivate carbapenems) as well as additional groups that possess carbapenemase [1,12]. Isolates within this class are characterized by their hydrolytic mechanism of beta-lactam inactivation, which requires an active-site serine at position 70 [13].

The most clinically important carbapenemase within this class is the Klebsiella pneumoniae carbapenemase (KPC) group:

Klebsiella pneumoniae carbapenemases (KPC) — The genes that encode KPCs reside on transmissible plasmids and confer resistance to most beta-lactams [14]. Because KPC genes reside on plasmids, they can be transmitted from Klebsiella to other genera, including E. coli, Citrobacter, Salmonella, Serratia, Enterobacter spp, and Pseudomonas [15-20].

KPC-possessing CRE have been increasingly recovered from multiple regions of the world, including North America, Europe, Asia, Australia, South America, and South Africa [15,16,21-28].

In the United States, KPCs are the most common carbapenemase [29]. Since the first description of KPC from a clinical isolate of K. pneumoniae in the late 1990s in North Carolina, KPC-production has been identified in isolates from nearly every state [14,30,31]. In a review of 4440 CRE isolates submitted to the United States Centers for Disease Control and Prevention (CDC) in 2017, 32 percent produced a carbapenemase and, among those, 88 percent possessed a KPC carbapenemase [29].

Several different variants of KPC enzymes have been identified, each of which may have different susceptibility profiles when tested in vitro [32,33].

Chromosomally-encoded Class A carbapenemases include Serratia marcescens enzyme (SME), NMC (non-metalloenzyme carbapenemase), and IMI (imipenem-hydrolyzing) beta-lactamases; SME have been recovered in a small number of S. marcescens isolates, while NMC and IMI have been identified among Enterobacter spp [32-34]. Plasmid-encoded enzymes other than KPC include Guiana extended-spectrum (GES) and BKC-1; GES has been described in P. aeruginosa and K. pneumoniae, and BKC-1 has been detected in K. pneumoniae isolates in Brazil [12,14,35-37].

Class B beta-lactamases — Class B beta-lactamases are also known as the metallo-beta-lactamases (MBLs). MBLs are named for their dependence on zinc for efficient inactivation of beta-lactams and all are carbapenemases.

MBLs were initially described in Japan in 1991 [38]. MBLs have since been described in other parts of Asia, Europe, North America, South America, and Australia [39-44]. The greatest burden of MBLs is in South and Southeast Asia (eg, India, Pakistan, China), and MBLs are the predominate carbapenemase in India, Pakistan, and some eastern European countries (eg, Greece, Hungary, Serbia, Croatia) [45]. The transfer of patients between hospitals and the increase in international travel may be important factors in the geographic dissemination of MBL genes [39,40,46-48].

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 [39]. Acquired MBLs consist of genes encoded on integrons residing on large plasmids that are transferable between both species and genera [13,46,49-53]. For example, in a hospital outbreak involving 62 patients, an MBL gene (bla-IMP-4) spread among seven different gram-negative genera (Serratia, Klebsiella, Pseudomonas, Escherichia, Acinetobacter, Citrobacter, and Enterobacter) [49,54].

The most clinically important Class B carbapenemase is the New Delhi metallo-beta-lactamase (NDM-1):

New Delhi metallo-beta-lactamase (NDM-1) – Isolates that produce NDM-1 carbapenemases are resistant to a number of antibiotics, including antibiotics to which other types of carbapenemase-producing isolates are susceptible (eg, newer beta-lactamase inhibitor combination antibiotics) [55].

The gene encoding NDM-1 is embedded within 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 [56,57]. NDM-1 has been identified in Enterobacterales (eg, K. pneumoniae, E. coli, Enterobacter cloacae) and non-Enterobacterales (eg, Acinetobacter) species [58,59].

The NDM-1 gene was first described in December 2009 in a K. pneumoniae isolate from a Swedish patient who had been hospitalized in India [56]. Spread of this carbapenemase quickly ensued, and pathogens with NDM beta-lactamases have since been reported throughout the world, including in Asia, Europe, North America, the Caribbean, and Australia [57,58,60-65]. The highest prevalence is in India, Pakistan, and Bangladesh, and high prevalence is also reported in Eastern European countries (eg, Romania, Poland, Serbia) [45,66]. There have also been reports of patients who traveled internationally for health care procedures (so called "medical tourism") and presented with NDM-1 infections after returning to their home country [58].

In the United States, initial reports of NDM-1-producing Enterobacterales isolates were among patients who had traveled to India or Pakistan [63]. However, by 2017, NDM-1 was found in 3.2 percent of CRE isolates submitted to the CDC's National Healthcare Safety Network, suggesting this beta-lactamase has become established in North America [29].

The first MBL discovered in 1991 was an IMP-1 MBL [38]. Since then, additional groups of acquired MBLs have been identified: NDM, VIM, GIM, SPM, SIM, and other IMPs. There are a number of variants within each MBL group (for example, there are more than 50 IMP variants within the IMP group) [39,67].

As a result of their dependence on zinc, MBLs can be inhibited by EDTA (an ion chelator); however, they are not inhibited by beta-lactamase inhibitors such as tazobactam, clavulanate, sulbactam, avibactam, vaborbactam, and relebactam.

Class C beta-lactamases – Class C beta-lactamases are also known as AmpC beta-lactamases. Bacteria within the Class C group do not inherently have significant carbapenemase activity. AmpC-producing isolates are discussed elsewhere. (See "Extended-spectrum beta-lactamases".)

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 [68]. OXA-type carbapenemases have been identified in CRE isolates, especially K. pneumoniae, E. coli, and E. cloacae [68-78].

Among the heterogeneous OXA group (which includes more than 100 enzymes), six subgroups have been identified with varying degrees of carbapenemase activity: OXA-23, OXA-24/OXA-40, OXA-48, OXA-51, OXA-58, and OXA-143 (table 1). All groups are carried on transmissible plasmids except for OXA-51, which is chromosomally encoded (in Acinetobacter baumannii).

The most clinically important Class D carbapenemase is the OXA-48-type carbapenemase:

OXA-48-type carbapenemase (OXA-48-type) – The first OXA-48-type carbapenemase was identified in a K. pneumoniae isolate in Turkey. Isolates have since been discovered in regions around the world including the United States, Europe, the Middle East, and Northern Africa [28]. Based on available data, they have the highest prevalence in Turkey and other Mediterranean countries (eg, Spain, France, Romania) [66]. In 2017, 1.6 percent of CRE in the United States were found to possess OXA-48-type carbapenemases [29].

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 [47,54,79]. As an example, in one case-control study, 86 percent of patients with a KPC-producing Enterobacterales isolate (n = 91) had a history of cephalosporin use in the prior three months [80]. However, prior receipt of antibiotics is not essential for acquisition of these strains [23,24].

In addition to prior antibiotic use, other risk factors that have been associated with infection or colonization with a carbapenemase-producing organism include the following [17,19,24,26,49,57,81-87]:

Prior colonization or infection with a carbapenemase-producing organism

Recent travel (ie, within the prior 12 months) to countries with high prevalence of carbapenemase-producing organisms (eg, India, Greece, Pakistan, Turkey, Croatia), particularly if health care exposure occurred in the country (see 'Classifications and geographic distribution' above)

Trauma

Diabetes

Malignancy

Organ transplantation

Mechanical ventilation

Indwelling urinary or venous catheters

Overall poor functional status or severe illness

Residence in a long-term care facility

Limited data suggest that intestinal colonization with organisms carrying certain types of carbapenemases may be more likely to lead to bloodstream infections than colonization with other types of carbapenemases. Further data are necessary to confirm or refute this finding [88].

Transmission — The rapid spread of CRE around the world is due to a combination of molecular spread of carbapenemase genes among different strains of bacteria and the creation of environments where bacteria themselves can easily proliferate and spread to individuals.

Transmission of carbapenemase genes from one bacterium to another – Carbapenemase genes can be transferred from carbapenemase-producing bacteria to other bacteria via vertical or horizontal transfer:

Vertical transfer occurs when a carbapenemase gene is transferred from a parent bacterial cell to its offspring during reproduction. Because bacterial reproduction occurs via cell division and does not require two parent cells, daughter bacterial cells have a genetic profile that is essentially identical to their parent. Thus, daughter cells always inherit a carbapenemase gene if their parent is a carrier (unlike mammalian reproduction in which children have only a 50 percent chance of inheriting a specific gene from a parent).

Horizontal carbapenemase gene transfer occurs when two different bacteria within close proximity to each other transfer genes. Horizontal carbapenemase transfer can occur within species or among different genera, as described above. (See 'Classifications and geographic distribution' above.)

Horizontal transfer typically occurs via transfer of a mobile genetic element (usually a plasmid) that harbors the carbapenemase gene. Once a carbapenemase-gene-carrying plasmid is acquired via horizontal transfer, it can further proliferate via vertical transmission during bacterial cell division (plasmids are copied during bacterial cell division, just as chromosomal DNA is copied).

Because of the combination of vertical and horizontal transfer, carbapenemase genes can spread rapidly within bacteria-rich environments, such as patients' stool and community sewage systems. Furthermore, environments where broad-spectrum antibiotics are used (eg, hospitals, domestic livestock farms) can select for carbapenemase-producing isolates and thereby produce an environment ripe for proliferation of carbapenemase-producing organisms [89-91].

Transmission of CRE to humans – Humans typically acquire CRE, like other gram-negative bacilli, by direct physical contact with the bacteria. People come into contact with the bacteria by touching either a person who has CRE or an environmental surface or substance contaminated with CRE. Once individuals acquire CRE, they often shed the bacteria in their stool and contaminate themselves and their surrounding environment [39,53,92,93].

There are many reports of the introduction of carbapenemase-producing CRE into a country via hospitalization of an individual who recently returned from travel to a country with high prevalence of CRE [57,87,94]. Once imported into a hospital, carbapenemase-producing CRE can proliferate [17,49,82,84-86]. Identified sources of spread within hospitals include poor hand hygiene, hospital equipment such as stethoscopes and endoscopes, and colonized sinks and toilets [41,53,95].

Carbapenemase-producing bacteria have also been found to be prevalent in public water supplies in resource-poor countries and countries where over-the-counter antibiotics are common [28,96]. For example, in India, contamination of the public water supply with NDM-1-positive bacteria is believed to contribute to high rates of human infection and colonization with these bacteria among residents and travelers to the country [94].

Once introduced into a new environment, specific clones of carbapenemase-producing CRE can become well established within and outside the health care system [41,49,54,97]. One particular clone of K. pneumoniae that carries the KPC gene has been reported as the predominant isolate across several geographic areas [28].

DETECTION OF CRE AND CARBAPENEMASES

CRE detection — Detection of CRE isolates is usually not difficult because most isolates are typically identified using standard susceptibility results reported by microbiology laboratories. Specifically, CRE is confirmed by resistance of an Enterobacterales isolate to at least one carbapenem (except for Proteus, Morganella, and Providencia, for which imipenem resistance is intrinsic). Further discussion of the definition of CRE and the Enterobacterales order is found elsewhere. (See 'Carbapenem-resistant Enterobacterales' above and 'The Enterobacterales order' above.)

Carbapenemase detection — Identification of a CRE isolate does not always mean that the isolate produces a carbapenemase, but it should raise clinical suspicion. Furthermore, a carbapenemase-producing organism should be suspected in any patient with CRE who has previously grown a carbapenemase-producing isolate in culture or who has traveled within the prior 12 months to a country with a high prevalence of carbapenemase-producing bacteria, particularly if health care exposure occurred during travel [98]. (See 'Risk factors' above.)

Determining whether a carbapenemase is present can be important for infection control purposes and because it may in some cases affect antibiotic selection, as discussed elsewhere. (See 'Antibiotic selection' below.)

Detecting the presence of a carbapenemase in a CRE isolate is not always straightforward, and microbiology laboratories vary in their practices. Standard susceptibility testing cannot confirm the presence of a carbapenemase because susceptibility patterns of carbapenemase-producing isolates and noncarbapenemase-producing CRE isolates can be identical [32-34].

However, CRE isolates that are also resistant to some of the newer extended-spectrum antibiotics may be suspected of harboring a specific carbapenemase. For example, ceftazidime-avibactam resistance may suggest a class B beta-lactamase. Rarely, CRE isolates retain susceptibility to aztreonam, a finding that is suggestive of a metallo-beta-lactamases (MBL) carbapenemase (although MBL-producing organisms are usually reported as resistant to aztreonam).

Laboratories typically confirm carbapenemase production in a CRE isolate by performing phenotypic or genotypic tests that go beyond standard susceptibility testing:

Phenotypic tests – These tests utilize basic culture techniques that can be performed by typical microbiology laboratories. The tests detect specific characteristics of carbapemenase-producing organisms by using certain reagents or susceptibility testing methods [39,46,99-107]. If positive, these tests can confirm the presence of a carbapenemase, but negative results may not reliably exclude their presence. The tests typically cannot distinguish between types of carbapenemases, but some phenotypic tests can help to differentiate class B beta-lactamases from others.

Genotypic tests – Unlike phenotypic tests, genotypic tests use molecular methods, such as polymerase chain reaction (PCR), to detect the presence of carbapenemase genes or gene mutations within a bacterial isolate. They are typically used to provide rapid results on isolates growing in blood or other sterile sites. The results of these tests often return before susceptibility testing and other phenotypic tests and may improve the use of appropriate therapy in infected individuals.

Because they detect specific genes, genotypic tests can identify specific carbapenemases, such as Klebsiella pneumoniae carbapenemase (KPC), New Delhi metallo-beta-lactamase (NDM-1), or OXA-48-type carbapenemases. Because genotypic tests are so specific, individual genotypic tests must be run for each individual carbapenemase. To overcome this issue, genotypic tests are often run as panels which allow multiple individual tests to be performed during a single cycle of testing. Such tests can screen at once for KPCs, individual MBLs, and OXA-type carbapenemases [49,71,108-114].

Drawbacks of genotypic tests include negative results when a particular panel does not include a specific carbapenemase carried by the organism. Additionally, special equipment is necessary to run these tests.

CLINICAL DISEASE — CRE can cause clinical infections or asymptomatic colonization [19,23]. Bloodstream infections, ventilator-associated pneumonia, urinary tract infection, and central venous catheter infections have been described [41,49,53,105]. These organisms have been isolated from respiratory tract specimens, abdominal swabs, catheters, abscesses, urine, and surgical wounds [23,41,53,54,105,115,116].

The specific clinical syndromes are discussed in more detail in the corresponding topic reviews.

APPROACH TO TREATMENT — The optimal treatment of infection due to CRE is uncertain, and antibiotic options are limited (algorithm 1). Management of patients with such infections should be done in consultation with an expert in the treatment of multidrug-resistant bacteria.

Requesting specific susceptibility tests — When a CRE isolate is confirmed, including carbapenemase-producing Enterobacterales isolates, we typically request susceptibility testing for the following additional antibiotics to help guide antibiotic selection:

Agents that contain newer beta-lactamase inhibitors (ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-cilastatin-relebactam ) [117,118]

Cefiderocol

Aminoglycosides (particularly plazomicin, if available)

Fluoroquinolones and trimethoprim-sulfamethoxazole (TMP-SMX; if not already reported)

Colistin or polymyxin B

Aztreonam

Tetracyclines including minocycline, tigecycline, and eravacycline (if available)

Fosfomycin and nitrofurantoin (for urinary tract isolates)

For suspected or confirmed metallo-beta-lactamase (MBL)-carrying organisms, testing for synergy between ceftazidime-avibactam and aztreonam should also be requested if possible [119].

Indications for empiric coverage of CRE — In patients who are suspected of having an infection due to gram-negative bacilli, we only include coverage for CRE in selected high-risk cases. Specifically, we provide empiric therapy to patients with serious illness (eg, ventilator-associated pneumonia, intraabdominal infection) who have had exposure to an outbreak setting (eg, an intensive care unit with a CRE outbreak) or have had a prior culture at the site of infection that grew CRE. In such cases, an antibiotic regimen should be chosen that is directed toward the suspected isolate. Specific regimens are discussed below. (See 'Antibiotic selection' below.)

Antibiotic selection — When a CRE infection is identified, we select or tailor the antibiotic regimen based on the susceptibility profile (algorithm 1).

Isolates susceptible to standard-spectrum antibiotics — Although susceptibility of CRE to traditional standard-spectrum antibiotics is uncommon, they can be used if the isolate is susceptible. Such antibiotics include fluoroquinolones and TMP-SMX. For urinary tract infections (UTIs), aminoglycosides, nitrofurantoin, and fosfomycin are additional possibilities (algorithm 1).

Most CRE isolates are reported as nonsusceptible to traditional beta-lactams (eg, piperacillin-tazobactam, ceftriaxone, cefepime). Even if a CRE isolate is reported as susceptible to a traditional beta-lactam, we typically do not use the agent. We will treat with aztreonam in the unusual instance that an MBL-producing isolate is reported as susceptible to aztreonam, as discussed elsewhere [120]. (See 'Carbapenemase detection' above.)

Not uncommonly, CRE isolates are reported as susceptible to meropenem and imipenem-cilastatin but resistant to ertapenem [121]. Technically, these isolates are still categorized as CRE, as defined above (see 'Carbapenem-resistant Enterobacterales' above). Most of these isolates do not contain a carbapenemase, and we treat them with standard-spectrum antibiotics if possible [10,98,121,122]. If standard-spectrum antibiotics are not an option, we cautiously use a carbapenem to which the isolate is susceptible. If these isolates test positive for a carbapenemase, we treat them as if they are resistant to all carbapenems regardless of susceptibility results [98,123-125]. (See 'Carbapenemase testing is positive' below.)

Fluoroquinolones – For infections due to susceptible isolates, fluoroquinolones (eg, ciprofloxacin, levofloxacin) can be used as monotherapy. Oral and intravenous formulations are available, and dosages are listed in the table (table 2).

Clinical studies of fluoroquinolones for treatment of CRE infections are limited, but the agents are commonly used to treat infections caused by carbapenem-susceptible Enterobacterales, and there is no reason to suspect they would be ineffective against fluoroquinolone-susceptible CRE.

Unfortunately, the use of these agents for CRE infections is limited due to high rates of resistance. Depending on the study, resistance rates of CRE isolates to fluoroquinolones range from 25 to 98 percent [39,53,126-128].

Trimethoprim-sulfamethoxazole – Like fluoroquinolones, trimethoprim-sulfamethoxazole (TMP-SMX) can be used as monotherapy to treat infections caused by susceptible isolates, and it can be given orally or intravenously. Dosages are listed in the table (table 2).

Clinical data regarding use of TMP-SMX to treat CRE infections are scarce, but we use it to treat susceptible CRE infections at any site.

Resistance to TMP-SMX is common among CRE isolates. In one study of 476 patients who had CRE infections from 18 hospitals in the United States, 338 (71 percent) had isolates that were nonsusceptible to TMP-SMX [129]. Like other antibiotics, emergence of resistance while on therapy appears to hamper TMP-SMX's efficacy over time.

Aminoglycosides – Due to associated toxicity (eg, nephrotoxicity, ototoxicity), we typically avoid the use of aminoglycosides in favor of other active agents, if possible.

These agents can be used as monotherapy for susceptible CRE UTIs when other options are limited. They should not be used as single agents for infections outside the urinary tract due to lack of supportive clinical data in these settings [98]. Dosages are listed in the table (table 2).

For select patients with simple cystitis in whom complicated UTI has been ruled out, a single dose of an aminoglycoside is likely to be adequate and avoid associated toxicity. For patients with complicated UTIs, longer durations are often necessary, which may increase the risk of renal and ototoxicity, as discussed separately. (See "Acute complicated urinary tract infection (including pyelonephritis) in adults and adolescents", section on 'Duration' and "Aminoglycosides", section on 'Toxicity'.)

Based on observational data, aminoglycosides appear to be effective for treatment of CRE UTIs. In a study of 87 patients hospitalized in New York with carbapenem-resistant K. pneumoniae bacteruria, treatment with an aminoglycoside was associated with a higher rate of microbiologic clearance (88 percent) compared with either polymyxin B (64 percent) or tigecycline (43 percent) [130].

CRE isolates are often susceptible to at least one aminoglycosides (eg, gentamicin, tobramycin, amikacin, plazomicin) [131]. Plazomicin often retains activity against CRE isolates that are resistant to all other aminoglycosides. In the United States, plazomicin is approved for treatment of complicated UTIs in adults, but overall, clinical data using plazomicin to treat systemic infections due to carbapenem-resistant pathogens are limited [132].

Nitrofurantoin – Nitrofurantoin is an effective agent for simple cystitis, but it should not be used for complicated UTIs (eg, pyelonephritis) or for infections outside the urinary tract. The dosage is listed in the table (table 2).

CRE isolates are sometimes resistant to nitrofurantoin. For example, in a study of 81 carbapenem-resistant E. coli urine isolates from India, 37 (45 percent) were nonsusceptible [133].

Fosfomycin – We only use fosfomycin monotherapy (3 g orally as a single dose) to treat simple cystitis caused by E. coli. The dosage is found in the table (table 2).

Data, including randomized trials, suggest that fosfomycin is an effective agent for simple cystitis, including that caused by multidrug-resistant gram-negative bacilli [134]. However, for organisms other than E. coli, intrinsic resistance mechanisms may be present and lead to clinical failure [135,136].

According to United States and European standards, susceptibility results for fosfomycin can be reported only for E. coli isolates [137,138]. Furthermore, special microbiology methods are required to detect resistance. In vitro resistance appears to be uncommon among CRE isolates [134,136,139-141]. However, emergence of resistance while on therapy has been documented [134,142].

In addition to its oral formulation, fosfomycin is also available in some countries in an intravenous formulation (not available in the United States). Sufficient data are lacking for the use of intravenous fosfomycin for infections outside the urinary tract; available studies included the agent as part of combination regimens, and no discernible conclusions could be made [143,144]. Furthermore, caution is warranted when using the agent for monotherapy outside the urinary tract because of its potential to develop resistance during treatment.

Minocycline – We rarely use minocycline to treat CRE infections because data regarding the clinical use of minocycline to treat such infections are scarce; in a few case reports, minocycline was successful as monotherapy or as part of combination therapy in the treatment of health care-associated pneumonia, intra-abdominal infection, and bacteremia due to CRE [145,146]. The dosage is found in the table (table 2).

Minocycline susceptibility of CRE isolates varies, ranging from 12 percent susceptibility of Klebsiella pneumoniae carbapenemase (KPC)-producing isolates in Detroit, Michigan to 65 percent susceptibility of NDM- and OXA-48-type-producing isolates in India [146,147].

Isolates resistant to standard-spectrum antibiotics — For isolates that are resistant to standard-spectrum antibiotics, monotherapy with a newer extended-spectrum agent is preferred (algorithm 1). These agents are generally well tolerated [148-157].

If such agents are not available, combination therapy with other agents is an alternative option, but we do not combine the newer extended-spectrum agents with other antibiotics except in rare circumstances, as described below. (See 'Limited role of combination therapy' below.)

Carbapenemase testing not available — Antibiotic selection for CRE isolates should be based on susceptibility results, whenever possible. As described above, susceptibility results can sometimes be used to determine the likelihood of specific carbapenemases and thereby guide therapy (see 'Carbapenemase detection' above). Additionally, local rates of carbapenemase production, if available, can be useful (algorithm 1).

In the United States, KPCs are the most common carbapenemases [10,11]. Thus, unless we have reason to suspect another type of carbapenemase, we presume a KPC-mediated mechanism in CRE isolates and treat accordingly.

If an MBL or OXA-48-type carbapenemase is suspected, we treat for the suspected carbapenemase (see 'Carbapenemase testing is positive' below). We have a high suspicion for such organisms in patients with CRE who have previously had a culture that grew an MBL- or OXA-48-type-producing isolate, have a susceptibility profile suggestive of these carbapenemases, or have traveled within the prior 12 months to a country with a high prevalence of such isolates, especially if medical care was received while there [45]. Details regarding the epidemiology and risk factors for different types of carbapenemases is discussed above. (See 'Carbapenemases' above.)

Carbapenemase testing is negative — Depending on local epidemiology, many CRE isolates do not produce a carbapenemase (or produce a carbapenemase that is not readily detected by local laboratory techniques). In the United States, approximately 40 percent of isolates resistant to all carbapenems do not harbor a carbapenemase, and these isolates usually retain susceptibility to the newer extended-spectrum agents discussed below (algorithm 1) [10,11]. (See 'Carbapenemase testing is positive' below.)

Carbapenemase testing is positive — When microbiologic testing confirms the presence of a carbapenemase, antibiotic options are based on susceptibility results and the specific carbapenemase if standard-spectrum antibiotics are not an option (algorithm 1). Standard-spectrum options are discussed above. (See 'Isolates susceptible to standard-spectrum antibiotics' above.)

If our suggested carbapenemase-specific regimens are not options, combination therapy can be used. (See 'Limited role of combination therapy' below.)

KPC – Preferred agents for KPC-possessing isolates are ceftazidime-avibactam or meropenem-vaborbactam; imipenem-cilastatin-relebactam is also an option, although there are fewer supporting data for this agent (algorithm 1). Cefiderocol is an effective alternative, but susceptibility testing is infrequently performed for this agent and we favor preserving it for isolates with non-KPC-mediated resistance. For intraabdominal infections, tigecycline and eravacycline are also acceptable alternatives. Dosages are listed in the table (table 2).

Ceftazidime-avibactam (see table (table 2) for dosage)

This agent has more clinical data supporting its use than the other newer agents because it was developed earlier. Observational data of patients with KPC-producing organisms often compare the agent to colistin, either in combination or as monotherapy. Overall, studies suggest that ceftazidime-avibactam is associated with improved clinical cure rates and reduced overall mortality compared to other traditional standard-spectrum agents [148,150,151,155-157].

-One observational study of 109 patients with KPC-producing K. pneumoniae bacteremia (97 percent due to KPC) found that patients treated with ceftazidime-avibactam were more likely to experience clinical success than patients treated with other therapies (OR 8.6; 95% CI, 1.6 to 43.4) [150]. The other therapies consisted primarily of a carbapenem combined with either an aminoglycoside or colistin. There was no difference in documented severity of illness, comorbidities, or source of infection between the two groups.

-Another observational study of 142 patients with KPC-producing bacteremia found that treatment with ceftazidime-avibactam was the only predictor of survival [155].

In vitro data suggest that ceftazidime-avibactam is active against over 95 percent of KPC isolates [158-160]. However, emergence of resistance to ceftazidime-avibactam during therapy has been reported and has been estimated to occur in approximately 20 percent of cases [98,149,161]. Some data suggest that KPC-producing isolates that become resistant to ceftazidime-avibactam during therapy may develop lower MICs to meropenem, although the clinical significance of this finding is unclear [161].

Meropenem-vaborbactam (see table (table 2) for dosage)

Data suggest that meropenem-vaborbactam is effective for CRE infections, although clinical data specifically focused on treatment of KPC-producing organisms are scarce.

-In a randomized controlled trial of 47 patients with serious CRE infections, meropenem-vaborbactam was associated with higher rates of clinical cure (66 percent) compared with best available therapy (33 percent); mortality rates were lower in the meropenem-vaborbactam group as well, although the mortality differences did not reach statistical significance [154].

-In an observational study of 131 patients with CRE infections, clinical cure and 30-day mortality rates were similar between patients treated with meropenem-vaborbactam and those treated with ceftazidime-avibactam (69 versus 62 percent, and 12 versus 19 percent, respectively) [149].

Resistance to meropenem-vaborbactam appears to be exceedingly uncommon among KPC-producing isolates, with in vitro data reports of 100 percent susceptibility [162,163]. Emergence of resistance during or after therapy has been estimated to occur in 3 percent of cases [98].

Imipenem-cilistatin-relebactam (see table (table 2) for dosage)

Clinical data evaluating this agent are scarce [98,152]. However, in vitro data, clinical experience, and the stability of relebactam against KPC-producing isolates suggest that this agent should be effective for isolates that test susceptible [158,159,164-167]. There are limited data available on the rate of emergent resistance to this agent during therapy.

Cefiderocol (see table (table 2) for dosage)

Cefiderocol is a siderophore cephalosporin that maintains activity against all of the major carbapenemases [168]. For CRE infections, data suggest that it is effective [98,153]. In the United States, it is approved for the therapy of complicated UTIs as well as hospital-acquired and ventilator-associated pneumonia.

Although cefiderocol is likely to be as effective as the other agents listed above for treatment of CRE, we favor other options so cefiderocol can be preserved for MBL- or OXA-48-type producing isolates or carbapenem-resistant gram-negative pathogens other than Enterobacterales [98].

Against KPC-producing CRE isolates, cefiderocol has been found to be active in vitro in over 95 percent of isolates [168]. There are scant data available on the frequency of emergent resistance to this agent while on therapy.

Tigecycline and eravacycline (see table (table 2) for dosages)

Clinical data evaluating the use of these agents for treatment of CRE isolates are scarce. In vitro data suggest that susceptibility rates of CRE isolates for both agents are typically above 95 percent, with similar susceptibility rates for KPC-producing isolates [160,162,169,170].

Carbapenems do not alter the activity of the tetracycline derivatives, including tigecycline and eravacycline. Therefore, active tetracycline derivatives should be expected to be no more or less effective against carbapenemase-producing isolates than noncarbapenemase isolates.

Both tigecycline and eravacycline have been found in randomized controlled trials for complicated intra-abdominal infections to achieve similar cure rates when compared with other appropriate agents [171-173].

Tetracycline derivatives, including tigecycline and eravacycline, should not be used to treat UTIs or bacteremia due to low urine and blood concentrations.

Omadacycline should not be used to treat CRE infections due to data suggesting high levels of baseline resistance to this agent [174].

OXA-48-type – The preferred antibiotic for isolates with an OXA-48-type carbapenemase is ceftazidime-avibactam (algorithm 1). Cefiderocol is an acceptable alternative. For intra-abdominal infections, tigecycline and eravacycline are also acceptable alternatives based on limited susceptibility data [169].

OXA-48-type CRE isolates have high rates of resistance to meropenem-vaborbactam and imipenem-cilistatin-relebactam. There is uncertainty about the utility of these agents for OXA-48-type-producing isolates reported as susceptible to these agents.

Observational data support the use of ceftazidime-avibactam for treatment of infections caused Enterobacterales isolates with OXA-48-type carbapenemases [157,175]. One study of 31 patients with hematologic malignancy and carbapenemase-producing E. coli bacteremia (19 with OXA-48-type and 12 with KPC carbapenemases) found higher clinical cure rates in patients who received ceftazidime-avibactam (86 percent) versus alternative active therapy (35 percent), and there was no difference in cure rates between OXA-48-type enzyme producers and KPC producers [157,175]. Efficacy data for cefiderocol, tigecycline, and eravacycline are further described above in the section discussing treatment of KPC-producing isolates.

In vitro data suggest that over 90 percent of OXA-48-type CRE isolates are susceptible to ceftazidime-avibactam, cefiderocol, tigecycline, and eravacycline [160,164,165,168,169,176]. However, studies report susceptibility rates of only 15 to 33 percent for imipenem-cilistatin-relebactam and 45 to 50 percent for meropenem-vaborbactam [164,165,167,176].

MBL – Antibiotics effective against isolates with MBL carbapenemases are limited because MBLs confer resistance to almost all beta-lactam-type antibiotics [118]. Based on growing evidence, the combination therapy with ceftazidime-avibactam PLUS aztreonam is preferred (algorithm 1). Another option is cefiderocol. For intra-abdominal infections, tigecycline and eravacycline are also acceptable alternatives based on limited susceptibility data [169]. If no other options are available, we occasionally resort to combination therapy with a polymyxin and at least one additional agent. (See 'Limited role of combination therapy' below.)

Ceftazidime-avibactam (as monotherapy), meropenem-vaborbactam, and imipenem-cilistatin-relebactam have no activity against MBL-producing organisms [159,160,163,165,167].

Ceftazidime-avibactam PLUS aztreonam (doses are listed in the table (table 2))

This combination has been successful in observational studies [177-180]. In a study of 102 patients with bacteremia due to MBL-producing Enterobacterales, 30-day mortality was lower for those treated with the combination of ceftazidime-avibactam and aztreonam compared with those who received alternative therapy (19 percent versus 44 percent, respectively) [180].

The combination of ceftazidime-avibactam PLUS aztreonam has a unique mechanism of action. MBL-producing organisms are intrinsically susceptible to aztreonam, but the organisms typically carry other resistance mechanisms (eg, ESBLs, AmpC beta-lactamases, OXA-48-type carbapenemases) that cause resistance to aztreonam [120]. By adding avibactam (a newer beta-lactamase inhibitor), these resistance mechanisms are overcome and aztreonam regains its activity. The ceftazidime component of ceftazidime-avibactam offers no additional benefit.

There are no laboratory standards to identify the rates of resistance of CRE isolates to this combination of antibiotics.

Cefiderocol (see table (table 2) for dosage)

Clinical experience in treating MBL-producing organisms with cefiderocol is extremely limited. In vitro data suggest that susceptibility rates of these organisms to cefiderocol are around 60 percent [168].

Efficacy data for tigecycline and eravacycline are further discussed above in the section discussing treatment of KPC-producing isolates.

Limited role of combination therapy — We generally avoid combination therapy for CRE infections; the lone exception is the combination of ceftazidime-avibactam and aztreonam for MBL-producing isolates, as discussed elsewhere (see 'Carbapenemase testing is positive' above). We generally do not combine the newer extended-spectrum agents with other antibiotics.

In select circumstances, however, combination therapy may be reasonable. Specifically, for serious CRE infections for which standard-spectrum and newer extended-spectrum agents are not options, combination therapy may be used. When utilized, combination therapy should include two active agents, and we suggest continuation of both agents for the full course of therapy. Antibiotics that can be considered for combination therapy include the following if susceptibility is confirmed: a polymyxin (ie, polymyxin B or colistin), tigecycline, eravacycline, aminoglycosides, and fluoroquinolones. Meropenem is sometimes used as part of combination therapy for isolates with MIC ≤8 (even if the isolate is reported as nonsusceptible). Eravacycline or tigecycline is typically combined with a second agent when they are being used for infections outside the abdomen. For E. coli infections, intravenous fosfomycin is also an option in some countries.

Prior to the availability of newer extended-spectrum antibiotics, polymyxins (ie, colistin or polymyxin B) were commonly used as part of combination therapy for CRE infections. However, observational data and randomized controlled trials indicate increased mortality and renal toxicity associated with these agents relative to comparator agents [98,148,150-152,154-157,175]. Concerns about the clinical effectiveness of polymyxins and the accuracy of susceptibility testing of polymixins against CRE isolates led American and European experts to eliminate or warn against susceptibility breakpoints for these agents [137,138].

Duration of therapy — Regardless of the site of infection, the duration of therapy is identical to that for infections caused by carbapenem-susceptible Enterbacterales isolates. Specifically, the duration depends on the site of infection, which is discussed in detail in separate topics. (See "Acute complicated urinary tract infection (including pyelonephritis) in adults and adolescents", section on 'Duration' and "Gram-negative bacillary bacteremia in adults", section on 'Duration and route of therapy' and "Antimicrobial approach to intra-abdominal infections in adults", section on 'Duration of therapy' and "Treatment of hospital-acquired and ventilator-associated pneumonia in adults", section on 'Duration'.)

PROGNOSIS — Prior to the availability of newer extended-spectrum treatment options, patients with CRE infections had worse outcomes than patients infected with carbapenem-susceptible isolates [89,181-183]. In a 2021 systematic review and meta-analysis of 50 studies, the risk of death was higher in individuals infected with CRE compared with carbapenem-susceptible Enterobacterales (relative risk [RR] 2.14; 95% CI, 1.85 to 2.48), and attributable mortality rate (available from eight studies) was 43 percent [183]. The systematic review found conflicting results when analyzing whether delay in appropriate antibiotic therapy (a common occurrence with CRE) was the primary driver of mortality.

Infections with carbapenemase-producing bacteria may have a particularly poor prognosis [122,184-187]. Compared with patients who have bacteremia due to carbapenemase-negative CRE, patients with bacteremia due to carbapenemase-producing pathogens have been found to have a three- to five-fold higher mortality [122].

Since the advent of newer extended-spectrum treatment options in 2015, beginning with ceftazidime-avibactam, it is unclear how attributable mortality has been affected. In one systematic review and meta-analysis of 11 studies comparing ceftazidime-avibactam with other treatment options, 30-day overall mortality was lower in the ceftazidime-avibactam group (RR 0.55, 95% CI 0.45 to 0.68); overall mortality in the ceftazidime-avibactam group was 26 percent and attributable mortality was not reported [188]. Further discussion of outcomes with newer agents is found elsewhere. (See 'Carbapenemase testing is positive' above.)

INFECTION PREVENTION — Infection prevention and control interventions can be divided into interventions related to health care environments and those related to communities.

Healthcare settings – Hospitalized patients infected or colonized with carbapenemase-producing bacteria should be placed on contact precautions [26,41,53,89,92,189,190]. Guidelines from the World Health Organization (WHO) and the Society of Healthcare Epidemiology of America recommend that inpatient contact precautions be continued for the duration of inpatient hospitalization [89,190]. Contact precautions should also be maintained indefinitely (ie, during future hospitalizations) given the prolonged colonization with such organisms and the limited treatment options. Other standard measures, such as hand hygiene, minimizing the use of invasive devices, and antimicrobial stewardship, are necessary to infection prevention in general and likely to limit spread of resistant organisms. Careful attention to disassembling, cleaning, and disinfection of endoscopes and replacement of poorly designed sinks and toilets can be important as well [95]. Further discussion of these interventions is found elsewhere. (See "Preventing infection transmitted by gastrointestinal endoscopy", section on 'Duodenoscopes' and "Infection prevention: Precautions for preventing transmission of infection".)

Screening high-risk patients to detect rectal colonization has been suggested as an important infection control modality [39,53,92,93]. Several studies have documented reduced transmission of Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae when comprehensive infection control protocols, including active surveillance, have been enacted [191-194]. Although the impact of surveillance itself is difficult to assess, it may be useful in the setting of outbreaks due to carbapenem-resistant organisms, as recommended by the United States Centers for Disease Control and Prevention (CDC) or among patients with recent travel to areas where carbapenemases are prevalent. Molecular tests that detect genes associated with carbapenem resistance can aid in detection of rectal colonization, although availability of these assays varies by country [195,196]. (See 'Carbapenemase detection' above.)

Communities – Interventions for communities suffering from high prevalence of CRE infections should consider specific interventions such as reducing over-the-counter antibiotic availability and broad-spectrum antibiotic use in livestock. Proper separation of sewage from the public water supply and public bodies of water is important. Environmental surveillance for CRE isolates can help to determine the extent of spread [96].

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Carbapenem-resistant enterobacterales (The Basics)")

SUMMARY AND RECOMMENDATIONS

Definitions – Carbapenem-resistant Enterobacterales (CRE) are any Enterobacterales (eg, E. coli, Klebsiella, Enterobacter, Serratia) that are resistant to at least one carbapenem (ie, ertapenem, meropenem, doripenem, or imipenem) or that produce a carbapenemase enzyme. Proteus, Morganella, and Providencia must be resistant to ertapenem, meropenem, and/or doripenem to be classified as CRE. (See 'Definitions' above.)

CRE can be divided into non-carbapenemase-producing and carbapemenase-producing isolates. (See 'Carbapenem-resistant Enterobacterales' above.)

Epidemiology – CRE, including carbapenemase-producing isolates, are becoming increasingly prevalent around the world. The most clinically important carbapenemases are Klebsiella pneumoniae carbapenemases (KPC), metallo-beta-lactamases (MBLs), and OXA-48-type carbapenemases (OXA-48-type), and their epidemiology varies significantly by country. In the United States, KPCs are the most common carbapenemase. (See 'Epidemiology' above.)

Detection of carbapenemases – Susceptibility profiles cannot reliably differentiate carbapenemase-producing and noncarbapenemase producing CRE isolates. Definitive tests include advanced phenotypic tests as well as genotypic tests, but these types of tests are not widely used. (See 'Carbapenemase detection' above.)

Antibiotic selection – Antibiotic selections for CRE are limited (table 2). Our suggested regimens are based on an isolate's susceptibility profile and results of carbapenemase testing, if available (algorithm 1). (See 'Antibiotic selection' above.)

Susceptible to standard-spectrum antibiotics – We use these agents if the isolate is susceptible (table 2 and algorithm 1). Such antibiotics include fluoroquinolones and trimethoprim-sulfamethoxazole (TMP-SMX). For urinary tract infections (UTIs), aminoglycosides, nitrofurantoin, and fosfomycin are additional possibilities. (See 'Isolates susceptible to standard-spectrum antibiotics' above.)

Resistant to all carbapenems – For isolates that are resistant to all standard-spectrum antibiotics as well as carbapenems, newer extended-spectrum agents are the primary options (algorithm 1). For intra-abdominal infections, tigecycline and eravacycline are acceptable alternatives (table 2). (See 'Isolates resistant to standard-spectrum antibiotics' above.)

-Carbapenemase testing not available – For these isolates, we use the susceptibility profile and the patient's risk factors to determine our level of suspicion for a KPC, MBL, or OXA-48-type carbapenemase; we treat presumptively for the suspected carbapenemase (algorithm 1). (See 'Risk factors' above and 'Carbapenemase testing not available' above.)

-Carbapenemase testing is negative – We suggest ceftazidime-avibactam, meropenem-vaborbactam, or imipenem-cilastatin-relebactam (table 2 and algorithm 1) (Grade 2C). Cefiderocol is an alternative. (See 'Carbapenemase testing is negative' above.)

-Carbapenemase testing is positive – Antibiotic regimens for these isolates are based on the specific carbapenemase (algorithm 1). (See 'Carbapenemase testing is positive' above.)

For KPC isolates, we suggest ceftazidime-avibactam, meropenem-vaborbactam, or imipenem-cilastatin-relebactam (table 2) (Grade 1C). Cefiderocol is an alternative.

For OXA-48-type isolates, we suggest ceftazidime-avibactam (table 2) (Grade 2C). Cefiderocol is an alternative.

For MBL isolates, we suggest treatment with a combination of ceftazidime-avibactam PLUS aztreonam (Grade 2C). Cefiderocol is a possible alternative (table 2).

Duration of therapy – The duration of therapy depends on the site of infection and is no longer for CRE infection than for other infections. (See 'Duration of therapy' above.)

Infection prevention – Patients infected with CRE should be placed on contact precautions, and other standard infection-control measures should be followed. In outbreak settings, additional measures are recommended. (See 'Infection prevention' above.)

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Topic 471 Version 68.0

References

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