Patients in intensive care units (ICUs) are susceptible to nosocomial infections due to underlying diseases, device use, and prior antibiotics use. Nosocomial infections are associated with morbidity, mortality, and increased costs [1,2]. An international study conducted in 1,265 ICUs from 75 countries showed that 51% (7,087/13,796) of patients were considered having infection according to the definitions of the International Sepsis Forum, and 71% were receiving antibiotics. Additionally, the infection rate of ICU patients was related to disease severity, and infection was independently associated with a greater risk of hospital mortality (adjusted odds ratio, 1.51; 95% confidence interval, 1.36–1.68; P<0.001) [2].

ICU patients are at a high risk of colonization and infection caused by multidrug-resistant organisms (MDROs). Patients with extended ICU stays have higher rates of infection by resistant organisms [2]. MDROs, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci (VRE), multi-drug resistant Acinetobacter baumannii (MRAB), and Enterobacterales that produce extended-spectrum β-lactamases (ESBL), are associated with ICU-related nosocomial infections [3]. Of these MDROs, Enterobacterales, an order of Gramnegative bacteria, harbor common pathogens for healthcare-associated infections, including pneumonia, bacteremia, and urinary tract infections. Recently, among MDROs, carbapenem-resistant Enterobacterales (CRE) have emerged as a threat for ICU patients [4] because of limited treatment options and high mortality rates [5]; therefore, CRE outbreaks, especially in the ICU, have become a critical issue. Several agents including ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, and imipenem-cilastatin-relebactam have been approved for clinical use [5], but these agents are not available in Korea. This study presents a review of the epidemiology, risk factors, clinical outcomes, and infection control of CRE in the ICU setting.

The Centers for Disease Control and Prevention (CDC) defines CRE as: (1) Enterobacterales that test resistant to at least one of the carbapenem antibiotics (i.e., minimum inhibitory concentrations of ≥ 4 µg/mL for doripenem, meropenem, and imipenem, and ≥ 2 µg/mL for ertapenem) or (2) Enterobacterales that produce a carbapenemase [6]. For Enterobacterales (Proteus species, Morganella spp., Providencia spp.) that may have intrinsic reduced susceptibilities to imipenem other carbapenem antibiotics should be used to test carbapenem resistance [6].

The “E” in CRE used to stand for the family Enterobacteriaceae but has been recently altered to the order Enterobacterales due to taxonomic changes [7]. If the older usage (Enterobacteriaceae) is to be persistently held, important genera like Proteus, Serratia, and Pantoea, despite their infrequent resistance to carbapenems, will be omitted from CRE.

One mechanism of resistance to carbapenem antibiotics in Enterobacterales is the production of carbapenemases, the enzymes that hydrolyze carbapenem antibiotics and are encoded by mobile genetic elements [8]. Approximately 30% of CRE are carbapenemase-producing CRE (CPE) that harbor the carbapenemases [9], which rapidly spread resistance [8].

The Ambler classification system, which is based on amino acid homology, shows four major classes of β-lactamases, viz., classes A, B, C, and D [10,11]. Classes A, C, and D β-lactamases share a serine residue in their active site (serine β-lactamases), while class B β-lactamases require zinc for their action (metallo-beta-lactamases, MBLs) [12,13]. Classes A, B, and D confer carbapenem resistance in Enterobacterales and have clinical importance for their role as healthcare-associated pathogens [5,12]. Clinically, the most significant class A carbapenemase is the Klebsiella pneumoniae carbapenemase (KPC) group [8]. Owing to the transmission from Klebsiella to other genera, KPC can be found in various Enterobacterales, including Escherichia coli, Citrobacter spp., Serratia marcescens, and Enterobacter spp. [12,14-17]. Clinically significant Class B carbapenemases are IMP (active on imipenem), Verona integron-encoded metallo-β-lactamase, and New Delhi metallo-β-lactamase (NDM) [10,12]. Class D carbapenemases are referred to as OXA carbapenemases due to their ability to hydrolyze oxacillin; OXA stands for oxacillinase [18]. There are many different variants or subtypes of carbapenemases, from KPC-1 to KPC-67, according to the order reported and amino acid substitutions [19-21].

The prevalence of CRE infection continues to increase globally [8]. In the United States, an active surveillance study showed that the overall annual incidence of CRE infection was 2.93 cases per 100,000 persons in seven U.S. metropolitan communities, and site-specific incidence rates ranged from 0.35 to 4.58 per 100,000 persons [22]. In a 2019 report, 13,100 cases of CRE infection were reported in the U.S., with 1,100 hospitalized patients deaths [23]. The first CPE reported was KPC-producing K. pneumoniae from North Carolina in 1996 [24], and by 2001, many reports of CPE from the northeastern U.S. had been published [25]. KPC-producing K. pneumoniae is mostly found in North America, Israel, Latin America, Italy, and Greece (Table 1) [8,25]. A CRE network study conducted in China in 2015 reported that the overall incidence of CRE infection was 4.05 per 100,000 patient-days (from 0.32 in Qinghai to 14.38 in Jiangsu), and 20.8% of CRE-infected patients were admitted to the ICU [26]. A study comprising active screening of CRE infections in hematology units in China reported that the CRE colonization rate in patients was 16.46% [27]. In a prospective cohort study of inpatients from the ICU and hematopoietic stem cell transplantation wards, the CRE colonization rate was 16.67% and KPC-producing K. pneumoniae was dominant [28]. National surveillance of CRE strains in China showed that KPC-2 and NDM were responsible for phenotypic resistance in 90% of CRE strains [29]. IMP-1, the first MBL, was reported in Japan in 1991 [30], and IMP is the carbapenemase found most abundantly in Japan [8,31]. A cross-sectional survey conducted in 22 acute care hospitals and 21 long-term care hospitals in Osaka, Japan reported that the carriage rate was 12.2% [32]. The first NDM-producing K. pneumoniae was discovered in 2009 in a patient who returned to Sweden from an Indian hospital [33]. NDM-producing organisms were found widely in Indian subcontinent and many European countries [12].

In Korea, the prevalence of CRE infection increased in 2015–2016 according to the national sentinel surveillance [34]. In June 2017, CRE infection was classified as a nationally notifiable communicable disease [35]. The reports of CRE infection cases have been increasing ever since. There were 11,954 cases in 2018, 15,369 in 2019, and 17,766 in 2020 [36]. In 2018–2019, the most commonly reported species was K. pneumoniae (51.9%–60.4%), the proportion of CPE in CRE was 49.8%–57.8%, and KPC was the most common carbapenemase. In a 2018, 1-year surveillance of CRE among 1,468 clinical isolates from hospitals in Seoul, K. pneumoniae and E. coli were the major isolates, 58.1% were CPE, and KPC-2 was the most commonly found carbapenemase [37]. In 2010, the first nosocomial clustering of NDM-1 producing K. pneumoniae occurred in a single tertiary hospital in Korea [38], and isolates with NDM subtypes were reported [37,39]. The percentage of patients infected with carbapenem-resistant organisms at a newly opened ICU was 2.3%–7.8% between 2005 and 2008 [40]. A study conducted in an emergency ICU setting in a tertiary hospital showed a 2.8% carriage rate at admission and a 2.6% (21/810) acquisition rate during the ICU stay (4.3 per 1,000 person-days) [41]. Among them, 42.9% were identified as CPE, and KPC was the most common carbapenemase. A recent study conducted in a medical ICU of an 816 bed hospital in Korea showed that 6.3% patients were positive for CRE from surveillance or clinical cultures, and the prevalence of CPE was 3.8% among ICU patients [42].

The presence of underlying comorbid conditions, prior antimicrobial exposure, indwelling catheters or devices, and prior use of healthcare facilities are major risk factors for CRE colonization (Table 2) [41-45]. These exposures are common during ICU stay; therefore, ICU stays themselves are a significant risk factor for CRE colonization [45]. The length of hospital or ICU stay has been found to be associated with CRE acquisition and colonization [41,45].

The use of carbapenem is a risk factor for CRE acquisition, but the proportion reported for carbapenem use among CRE-colonized patients varies from 15% to 75% [41,42,46,47]. The use of cephalosporins, β-lactams or β-lactams/β-lactamase inhibitors, aminoglycosides, fluoroquinolones, or glycopeptides is a risk factor for CRE colonization [41,42,45,48]. The cocolonization of MDROs including MRAB or ESBL-producing bacteria is more frequent in CRE colonized patients [41,43]. Since exposure to MDROs is frequent in healthcare settings, hospitalization within the previous 6–12 months and regular visits to outpatient clinics are major risk factors for CRE colonization [41,43,48,49]. A study predicting CRE carriage at the time of admission using the Illinois hospital discharge database showed that age, number of hospitalizations at shortterm acute care hospitals in the previous 365 days, length of hospital stay, and current admission to long-term acute care hospital (LTACH) are independent risk factors for CRE colonization [49].

Exposure to a long-term care facility (LTCF) is another significant risk factor for colonization of CRE. In four hospitals in a metropolitan area in the US, CRE colonization was detected in 8.3% of patients admitted from an LTCF, but it was 0% among community patients. Similarly, patients admitted from high-acuity LTCFs, e.g., skilled nursing facilities with ventilator care and LTACH, had 7.0-fold greater odds of colonization with KPC-producing CRE than patients from skilled nursing facilities without ventilator care [50]. The point prevalence of CRE colonization among patients admitted to LTCF in the District of Columbia in the US was 7.0% [51]. In Korea, the prevalence of CRE colonization in LTCFs is limited, but a report from national notifiable diseases showed that the proportion of CRE infection reported from nursing hospitals increased from 4.0% in 2018 to 10% in 2020 [52]. A recent study in a Korean hospital showed that previous admission in an LTCF was associated with CPE infection or colonization in the ICU [42]. Patients admitted from LTCF have a high risk of CRE carriage and can be a source of reintroduction of CRE to acute care hospitals because of the low number of well-trained infection control staff and limited facilities to control CRE [53].

Decreasing CRE acquisition in healthcare facilities is essential for infection control and may be an indicator of infection control in the hospital. Risk factors for acquisition include regular visits to the outpatient clinic, male sex, history of hospitalization within one year, and co-colonization with MRAB- or ESBL-producing bacteria [41,43].

Because treatment options are limited to few antibiotics and are often associated with delays or ineffective treatment, invasive infections caused by CRE are associated with a high mortality rate [48,54,55]. In a study including patients with CRE bacteremia, 22% of patients died within 14 days, and after adjusting for the severity of illness, underlying medical condition, and types of antibiotic treatment, the odds of dying within 14 days were 4.92 times greater for patients with CPE compared with those with non-carbapenemase producing CRE [56]. In another study conducted in a CRE epicenter in the US, 38% of patients with CRE bacteremia had septic shock, and 49% died within 30 days [57]. In a meta-analysis of mortality among hospitalized patients with a severe infection including pneumonia, complicated urinary tract infection, bacteremia, and complicated intra-abdominal infections attributable to CRE pathogens, CRE was associated with a significantly higher overall mortality (odds ratio, 3.39; 95% confidence interval, 2.35–4.89) [58].

Although CRE colonization can be detected on admission, clinical infection may not occur in some patients [41]. In a study on CRE acquisition rates in emergency ICUs, CRE acquisition was not an independent risk factor for in-hospital mortality [41]. However, in an observational cohort study conducted in New York City, 11% (36/338) patients were CRE-colonized at the time of admission. Of them, 47% developed a CRE infection within 30 days with a 10.8-fold increased odds of developing CRE infection at 30 days (95% confidence interval, 2.8–41.9) [48]. CRE colonization in critically ill patients is associated with at least a 2-fold increased risk of infection by the colonizing strain [54].

CRE colonization and infection are a significant problem in ICUs, and the prevalence of CRE is increasing. The CRE situation is serious in Korea as well as globally; CRE could become an endemic if not controlled. Strict infection control, including hand hygiene, contact precaution, device control, environmental cleaning, and early detection of CRE carriers with active surveillance methods, should be implemented in ICUs, and the attention of critical care staff is essential for controlling CRE.