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 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 IMI and NMC have been identified among Enterobacter isolates [6-8]. Plasmid-encoded enzymes include Klebsiella pneumoniae carbapenemase (KPC) and Guiana extended-spectrum (GES). GES has been described in Pseudomonas aeruginosa and K. pneumoniae [5,9-11]. (See 'Klebsiella pneumoniae carbapenemase' below.)
Klebsiella pneumoniae carbapenemase — The most clinically important of the Class A carbapenemases is the K. pneumoniae carbapenemase (KPC) group. These enzymes reside on transmissible plasmids and confer resistance to most 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 Escherichia coli, P. aeruginosa, Citrobacter, Salmonella, Serratia, and Enterobacter spp [14-19]. Another carbapenemase, BKC-1, has been detected in rare clinical isolates of K. pneumoniae in Brazil [20].
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); however, they are not inhibited by beta-lactamase inhibitors such as tazobactam, clavulanate, sulbactam, and avibactam. The first MBL, IMP-1, was described in Japan in 1991 [21]. 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 more than 50 IMP variants within the IMP group) [22,23].
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 [22]. Acquired MBLs consist of genes encoded on integrons residing on large plasmids that are transferable between both species and genera [4,24-29]. 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) [24,30].
New Delhi metallo-beta-lactamase (NDM-1) — Enterobacterales 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 K. pneumoniae [31]. Spread of this carbapenemase quickly ensued, and pathogens with NDM beta-lactamases have been reported throughout the world [32].
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 [31,33]. Furthermore, the large number of resistance determinants in the isolates studied raise concern that this gene is an important emerging resistance trait [34]. 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 Enterobacterales (including E. coli and Enterobacter cloacae) [35] as well as non-Enterobacterales (including Acinetobacter) [36].
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) [37]. Enzymes in this group are variably affected by the beta-lactamase inhibitors clavulanate, sulbactam, or tazobactam. OXA carbapenemases have been identified in Acinetobacter baumannii [37-46] and Enterobacterales (especially K. pneumoniae, E. coli, and E. cloacae) [47].
Among the heterogeneous OXA group (which includes more than 100 enzymes), six subgroups have been identified with varying degrees of carbapenem-hydrolyzing activity: OXA-23, OXA-24/OXA-40, OXA-48, OXA-58, OXA-143, and OXA-51 (table 1). The first five groups are carried on transmissible plasmids, while the last group, OXA-51, is chromosomally encoded. While most isolates of A. baumannii possessing an OXA-23, -24/40, or -58 type carbapenemase are resistant to carbapenems, Enterobacterales 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 [40].
EPIDEMIOLOGY
Distribution
Klebsiella pneumoniae carbapenemases — The K. pneumoniae carbapenemase (KPC) is the most common carbapenemase in the United States [48]. Following the first description of KPC from a clinical isolate of K. pneumoniae in the late 1990s in North Carolina [9,49], KPC-production has been identified in isolates from nearly every state [50]. In a review of 4440 carbapenem-resistant Enterobacterales 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 the KPC beta-lactamase [48].
KPC-possessing isolates have been increasingly recovered from other regions of the world, including Europe [51,52], Asia [14,53,54], Australia [55], South America [15,56], and South Africa [57].
Metallo-beta-lactamases — Metallo-beta-lactamases (MBLs) were initially described in Japan in 1991 [21]. MBLs have since been described in other parts of Asia, Europe, North America, South America, and Australia [22,58-62]. The transfer of patients between hospitals and the increase in international travel may be important factors in the geographical dissemination of MBL genes [22,28,58,63,64].
The MBL gene, the New Delhi metallo-beta-lactamase (NDM-1), was first described in December 2009 in a K. pneumoniae isolate from a Swedish patient who had been hospitalized in India [31]. Subsequent reports have included patients who have traveled and undergone procedures (so called "medical tourism") in India and Pakistan [35], as well as cases reported in Asia, Europe, North America, the Caribbean, and Australia [33,35,65-68].
In the United States, initial reports of Enterobacterales isolates with NDM-1 production had been among patients who had traveled to India or Pakistan [67]. However, by 2017, NDM-1 was found in 3.2 percent of carbapenem-resistant Enterobacterales submitted to the CDC's National Healthcare Safety Network, suggesting this beta-lactamase has become established in North America [48].
Isolates of P. aeruginosa which co-harbor genes for both KPC and NDM have also been described [69]. P. aeruginosa harboring VIM and IMP carbapenemases (other class B beta-lactamases) have also been recovered in the United States [48].
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 [37]. The first isolate of K. pneumoniae with OXA-48 was identified in Turkey; since then, hospital outbreaks from that country have been reported [70]. Enterobacterales with OXA-48-type enzymes have subsequently been recovered in the United States, Europe, the Middle East, and Northern Africa. In 2017, 1.6 percent of carbapenem-resistant Enterobacterales in the United States were found to possess OXA-48 [48].
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 [30,63,71]. 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 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 [72].
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 [53,54].
Additional risk factors that have been associated with infection or colonization with a carbapenemase-producing organism include the following [16,18,24,54,56,73-78]:
●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
Clinicians should be also aware of the possibility of NDM-1-producing Enterobacterales in patients who have received medical care in India and Pakistan [33,79]. (See 'Metallo-beta-lactamases' above.)
There is a report that the risk of carbapenem-resistant Klebsiella pneumoniae bloodstream infection in patients with rectal carriage varies with the type of carbapenemase [80]. In this study a higher risk of bloodstream infection was found with NDM compared with other carbapenemases.
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, Enterobacterales, 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 health care systems [70].
Limited data using DNA fingerprinting and pulse-field gel electrophoresis also suggest cross-transmission of bacteria with MBLs within hospitals [29]. This was illustrated in a study of 66 MBL-positive isolates from 54 hospitalized patients in a hospital outbreak [59]. 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 health care workers screened. The outbreak was curtailed following intensive environmental cleaning with hypochlorite, replacement of poorly designed sinks, and disassembling and cleaning of stethoscopes. Another outbreak of NDM-producing E. coli implicated contaminated endoscopes [81]. (See "Preventing infection transmitted by gastrointestinal endoscopy", section on 'Duodenoscopes'.)
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 [82]. In addition, two isolates of P. 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 [83].
Patients themselves may also serve as an important reservoir for resistant Enterobacterales, as intestinal colonization with carbapenemase-producing organisms has been reported [22,29,84,85].
DETECTION
Screening with susceptibility testing — Most K. pneumoniae and E. coli without carbapenemases have minimum inhibitory concentrations (MICs) to imipenem and meropenem that are below the current susceptibility breakpoint set by the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST). 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 Enterobacterales 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 (SME) in Serratia species and a non-metalloenzyme carbapenemase (NMC) or imipenem-hydrolyzing beta-lactamase (IMI) in Enterobacter species [6-8].
Once the susceptibility pattern suggests a carbapenemase, many laboratories will perform phenotypic testing followed by molecular identification of the carbapenemase. (See 'Phenotypic tests' below and 'Direct genotypic identification' below.)
P. aeruginosa and A. baumannii can become resistant to carbapenems without acquiring a carbapenemase; determining which isolates have an acquired carbapenemase based on susceptibility profiles can be difficult. In regions where metallo-beta-lactamases (MBLs) 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].
Phenotypic tests — Various phenotypic tests can be used to suggest the presence of particular carbapenemases in organisms. Inoculation on chromogenic agar can be used to screen surveillance cultures for carbapenemase-producing pathogens [87]. Using the inhibitory property of EDTA (an ion chelator) against MBLs, several phenotypic tests have been developed to screen isolates for these enzymes [22,28,88-90]. These tests include:
●The double-disc synergy test using carbapenem and EDTA discs
●Carbapenem discs with and without EDTA
●The commercially available MBL Etest [89-94]
●Carbapenem inactivation method [95]
Direct genotypic identification — Identification of specific carbapenemases can be accomplished utilizing molecular techniques [24,40,96-101]. These include multiplex polymerase chain reaction (PCR) assays and DNA microarrays that can screen at once for several different types of enzymes, including K. pneumoniae carbapenemases, specific MBLs, and OXA-type carbapenemases. Technology allowing for rapid identification of resistance genes, including carbapenemases, in blood cultures is being increasingly employed in microbiology laboratories [102]. (See 'Infection control' below.)
CLINICAL DISEASE — Carbapenemase-producing organisms can cause clinical infections or asymptomatic colonization [18,53]. Bloodstream infections, ventilator-associated pneumonia, urinary tract infection, and central venous catheter infections have been described [24,29,59,93]. These organisms have been isolated from respiratory tract specimens, abdominal swabs, catheters, abscesses, urine, and surgical wounds [29,30,53,59,93,103,104]. Sporadic hospital-acquired infections and outbreaks due to hospital-based clonal spread have been described in both tertiary and community hospitals [24,30,59,105].
The specific clinical syndromes are discussed in more detail in the corresponding topic reviews.
SUSCEPTIBILITY TESTING — In addition to resistance to the penicillins, cephalosporins, and carbapenems, resistance genes for other antibiotics, including aminoglycosides and fluoroquinolones, are frequently present in carbapenemase-producing strains [22,29]. For K. pneumoniae carbapenemase (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 [106].
When a carbapenemase-producing isolate is identified, additional antibiotic susceptibility testing should be requested for the following:
●Novel beta-lactam-beta-lactamase inhibitors (ceftazidime-avibactam, meropenem-vaborbactam, and/or imipenem-cilastatin-relebactam ) [107,108]
●Ceftolozane-tazobactam (particularly for P. aeruginosa) [109]
●Aminoglycosides (particularly plazomicin, if available)
●Colistin or polymyxin B
●Tigecycline and eravacycline (if available)
●Fosfomycin (particularly for urinary tract isolates)
For metallo-beta-lactamase (MBL)-carrying organisms, testing for synergy between ceftazidime-avibactam and aztreonam should also be considered [110].
TREATMENT — The optimal treatment of infection due to carbapenemase-producing organisms is uncertain, and antibiotic options are limited. Management of patients with infections due to carbapenemase-producing organisms should be done in consultation with an expert in the treatment of multidrug-resistant bacteria.
In outbreak settings, empiric therapy against carbapenemase-producing bacteria should be considered for patients with serious infections until culture and susceptibility data become available.
Therapy for carbapenemase-producing Enterobacterales
Serious infections — Therapeutic options for carbapenemase-producing Enterobacterales are limited, and no one antibiotic regimen has been clearly defined to be superior over another.
Preferred regimens — For most serious infections, the choice of therapy depends on the susceptibility profile of the isolate:
●Infections caused by organisms possessing a serine carbapenemase (eg, K. pneumoniae carbapenemase [KPC] or OXA-48) – For treatment of these infections, we suggest ceftazidime-avibactam, one of the other novel beta-lactam-beta-lactamase inhibitor combination agents (eg, meropenem-vaborbactam, imipenem-cilastatin-relebactam), or cefiderocol. Overall, clinical experience in treating carbapenemase-producing organisms with these agents is very limited; most has been with ceftazidime-avibactam. When beta-lactam agents are used for carbapenemase-producing isolates, prolonged-infusion dosing can be considered. (See "Prolonged infusions of beta-lactam antibiotics".)
If none of the beta-lactam agents listed above can be used, a polymyxin-based combination regimen, as detailed elsewhere, is appropriate as long as the isolate is susceptible. (See 'Alternative regimens' below.)
The novel beta-lactam-beta-lactamase combination agents have a better safety profile, more reliable dosing, and greater susceptibility rates compared with polymyxins. Efficacy data supporting their use are limited but promising [111-117]. As an example, in one retrospective study of patients with KPC-producing Enterobacterales, treatment with ceftazidime-avibactam was associated with a lower adjusted 30-day mortality rate compared with colistin [111]. However, these observational studies are subject to selection bias, and randomized controlled trials are warranted to confirm the observation. Moreover, emergence of resistance to ceftazidime-avibactam during therapy has been reported [118]. In vitro and in vivo evidence suggests adding a second agent (typically a carbapenem) may be synergistic [119,120]. Meropenem-vaborbactam and imipenem-cilastatin-relebactam also demonstrated in vitro and in vivo efficacy against KPC-producing isolates [121,122]. Cefiderocol is siderophore cephalosporin that maintains activity against bacterial isolates possessing a wide variety of beta-lactamases, including serine and metallo-carbapenemases [123], and it is approved for the therapy of complicated urinary tract infections (UTIs)as well as hospital-acquired and ventilator-associated pneumonia.
●Infections caused by isolates producing metallo-beta-lactamases (MBLs) – For such infections, we suggest an aztreonam-based regimen (typically aztreonam plus ceftazidime-avibactam) or cefiderocol. When beta-lactam agents are used for carbapenemase-producing isolates, prolonged-infusion dosing can be considered (see "Prolonged infusions of beta-lactam antibiotics"). If neither of these agents can be used, a polymyxin-based regimen should be used, as detailed elsewhere. (See 'Alternative regimens' below.)
MBLs confer resistance to all beta-lactam-type antibiotics except cefiderocol and aztreonam [108]. Although MBL-producing isolates often produce other extended-spectrum beta-lactamases that confer resistance to aztreonam, combining ceftazidime-avibactam and aztreonam can have a synergistic effect, as the avibactam can inactivate these other beta-lactamases to render the aztreonam active. This combination has been used to successfully treat a small number of patients with extremely resistant MBL-producing pathogens [124-126]. Clinical experience in treating MBL-producing organisms with cefiderocol is extremely limited.
Alternative regimens — When novel beta-lactams cannot be used for either serine-carbapenemase (eg, KPC or OXA-48) or MBL-producing Enterobacterales, we use a polymyxin (colistin or polymyxin B) with a second active agent [106,127]. A potential second agent is meropenem, especially if the isolate has an MIC to meropenem ≤8 mcg/mL. Tigecycline could also be a potential second agent, especially for infections involving the gastrointestinal tract and lungs, given its penetration into these tissues. Eravacycline tends to be more active than tigecycline against carbapenem-resistant Enterobacterales (CRE) and could be considered in the treatment of complicated intra-abdominal infections [128,129]. However eravacycline resistance is more common in multidrug-resistant isolates [129], and clinical experience with this agent (alone or in combination therapy) against CRE is very limited. Optimizing the dosing of polymyxins is discussed elsewhere. (See "Polymyxins: An overview", section on 'Intravenous administration'.)
The rationale for using two or more agents when a polymyxin-based regimen is being used includes the high mortality associated with serious CRE infections, evidence suggesting that combination therapy is associated with reduced mortality, and the concern for emergence of resistance during monotherapy. Several observational studies have suggested that treatment with combination therapy may improve mortality [130-137]. As an example, in a retrospective study of 661 patients with an infection due to K. pneumoniae confirmed by polymerase chain reaction to harbor the KPC gene, definitive therapy with combination therapy was associated with a lower 14-day mortality compared with therapy with a single active agent (30.2 versus 38.4 percent) [138]. Most combination regimens included a carbapenem; however, when the isolate had a meropenem MIC ≥16 mg/L, mortality rates among those who received a combination regimen with meropenem and those who received monotherapy were not statistically different [134]. An earlier analysis of a smaller subset of these patients reported that 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 g infused over three or more hours every eight hours) was associated with the lowest mortality rate (2 of 16 [12.5 percent]) [10,134].
Unfortunately, resistance to polymyxins is an increasing problem [139-145]. Development of polymyxin resistance in K. pneumoniae during polymyxin therapy has been documented [141], and the spread of isolates possessing the colistin resistance gene mcr-1 will likely further limit the utility of polymyxins [146]. Infection with a polymyxin-resistant strain has been found to be an independent risk factor for mortality [142,144]. (See "Polymyxins: An overview", section on 'Resistance'.)
Additional options for UTI
Complicated UTI — In addition to the above regimens (see 'Serious infections' above), several other options may be appropriate for treatment of complicated urinary tract infections (UTIs), depending on the susceptibility of the isolate and availability of the agent:
●Plazomicin, a novel aminoglycoside antibiotic with activity against many carbapenemase-producing isolates resistant to older aminoglycosides [147]. 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. A trial designed to compare plazomicin with colistin, each in combination with meropenem or tigecycline, for CRE bacteremia or ventilator-associated pneumonia was stopped early for slow enrollment; among the 39 patients who were randomized, rates of the composite outcome (death within 28 days or severe disease-related complications) were lower with plazomicin (24 versus 50 percent with colistin) [148].
●Parenteral fosfomycin, if available (not in the United States), may be an option to use in combination with other active agents if the isolate is susceptible, although we generally reserve it for use when other treatment options are limited. Fosfomycin susceptibility rates have been variable, ranging from 8 percent for KPC-producing K. pneumoniae to 74 percent for New Delhi metallo-beta-lactamase (NDM)-producing K. pneumoniae [149]. Fosfomycin cure rates (often when combined with other agents) among patients with CRE infections have ranged from approximately 50 to 95 percent [150-154].
Cystitis — Isolates causing acute simple cystitis can often be successfully treated with a single active agent, such as an aminoglycoside [107] or fosfomycin. Aminoglycosides can be given as a consolidated, extended-interval dose for 7 to 14 days, depending on response to therapy (see "Dosing and administration of parenteral aminoglycosides"). Fosfomycin can be given intravenously or as a single 3 g oral dose. Of note, intravenous fosfomycin is not available in many countries, including the United States.
Use of a single active agent in cystitis is supported by several small studies [154-156]. In one study of a panel of 81 carbapenem-resistant Enterobacterales of various types and species, 60 percent tested susceptible to fosfomycin [155].
Therapy for carbapenem-resistant A. baumannii and P. aeruginosa — Antibiotic selection for multidrug-resistant, including carbapenem-resistant, A. baumannii and P. aeruginosa is discussed in detail elsewhere:
●(See "Acinetobacter infection: Treatment and prevention".)
PROGNOSIS — Serious infections with carbapenemase-producing bacteria have a relatively poor prognosis [157-161]. Compared with patients who have bacteremia due to carbapenem-resistant (but not carbapenemase-producing) Enterobacterales, patients with bacteremia due to carbapenemase-producing pathogens have a three-fold higher mortality [157].
INFECTION CONTROL — Hospitalized patients infected or colonized with carbapenemase-producing bacteria should be placed on contact precautions [29,56,59,84,162]. Guidelines from the Society of Healthcare Epidemiology of America recommend that inpatient contact precautions be continued for the duration of inpatient hospitalization [163]. 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 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 [22,29,84,85]. 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 [164-167]. 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 more prevalent. Molecular tests that detect genes associated with carbapenem resistance can aid in detection of rectal colonization. Examples include the Xpert Carba-R assay (detects genes for KPC, NDM, VIM, IMP, and OXA-48) and the BD-MAX (detects genes for KPC, NDM, VIM, and OXA-48) [168,169]. Availability of these assays varies by country. (See "Infection prevention: Precautions for preventing transmission of infection".)
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 most clinically important Class A carbapenemase is the Klebsiella pneumoniae carbapenemase (KPC) group, which has been implicated in several outbreaks. (See 'Class A beta-lactamases' above and 'Klebsiella pneumoniae carbapenemase' 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. (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.)
●Escherichia coli or K. pneumoniae that have overt resistance to any of the carbapenems according to current Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) susceptibility breakpoints should be suspected of harboring a carbapenemase enzyme. In this setting, many laboratories perform phenotypic testing followed by molecular identification of the carbapenemase. Identifying strains of Pseudomonas aeruginosa or Acinetobacter 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, additional antibiotic susceptibility testing should be requested for novel beta-lactam-beta-lactamase inhibitor combinations (ceftazidime-avibactam, meropenem-vaborbactam, or imipenem-cilastatin-relebactam), colistin, aztreonam, tigecycline, eravacycline, cefiderocol, and fosfomycin. In addition, P. aeruginosa isolates should be tested for susceptibility to ceftolozane-tazobactam. (See 'Susceptibility testing' above.)
●For patients with serious infections due to carbapenemase-producing Enterobacterales, antibiotic selection depends on the type of carbapenemase and the susceptibility profile of the isolate (see 'Serious infections' above):
•For serine carbapenemases (eg, K. pneumoniae carbapenemase (KPC) and OXA-48), we suggest ceftazidime-avibactam if the organism is susceptible (Grade 2C). Meropenem-vaborbactam, imipenem-cilastatin-relebactam, and cefiderocol are other potential options. If none of these can be used, a polymyxin-based regimen is the alternative.
•For MBLs, we suggest either the combination of aztreonam with ceftazidime-avibactam or cefiderocol (Grade 2C). If neither of these can be used, a polymyxin-based regimen is the alternative.
•When a polymyxin (colistin or polymyxin B) is used, we suggest using a second active agent in combination with the polymyxin (Grade 2C). Potential second agents include meropenem or, for infections involving the gastrointestinal tract or lungs, tigecycline.
●Patients with acute simple cystitis caused by a carbapenem-resistant organism can often be successfully treated with a single active agent (eg, an aminoglycoside or fosfomycin). (See 'Cystitis' above.)
●Antibiotic selection for multidrug resistant, including carbapenem-resistant A. baumannii and P. aeruginosa are discussed in detail elsewhere. (See "Acinetobacter infection: Treatment and prevention" and "Pseudomonas aeruginosa pneumonia", section on 'Other strategies for drug-resistant isolates'.)
●Hospitalized patients infected or colonized with carbapenemase-producing bacteria should be placed on contact precautions for the duration of their hospitalization. Screening high-risk patients to detect rectal colonization may also be helpful in controlling transmission. (See 'Infection control' above.)
