Infections caused by multidrug-resistant (MDR) and extensively drug-resistant (XDR) Gram-negative bacteria (GNB) have become major challenges for global health institutions because of the limited antibiotic options and high mortality rates (Li et al., 2020; Chen H.Y. et al., 2021; Wang et al., 2021; Zhang et al., 2021b). Among the clinically important XDR-GNB species that harbor plasmidic genes encoding a wide variety of carbapenemases, isolates of sequence type (ST) 258, ST11, and ST147 Enterobacterales (mainly producing Klebsiella pneumoniae carbapenemase [KPC], metallo-β-lactamase [MBL, especially New Delhi MBL {NDM}], and oxacillinase [OXA], etc.), ST111 and ST235 Pseudomonas aeruginosa (mainly producing NDM, imipenemase [IMP], Verona integron-encoded MBL [VIM], and OXA, etc.), and ST2, ST32, ST92, and ST368 Acinetobacter baumannii complex (mainly producing MBL, NDM, and OXA, etc.), they usually co-harbor other resistant β-lactamases (various extended-spectrum β-lactamases [ESBLs] and/or AmpC β-lactamases), thus constitute a worrisome global threat because of their high potential for transmission (Tsakris et al., 2006; Vourli et al., 2006; Miriagou et al., 2007; Zappas et al., 2008; Giakkoupi et al., 2009; Da Silva et al., 2010; Kumarasamy et al., 2010; Papagiannitsis et al., 2010; Wang et al., 2010; Gupta et al., 2011; Chang et al., 2015; Huang et al., 2016; Roy Chowdhury et al., 2017; Yang et al., 2018; Nordmann and Poirel, 2019; Tavoschi et al., 2020; Yoon and Jeong, 2021). Similar to other surveys (Papadimitriou-Olivgeris et al., 2013; Lübbert et al., 2014), the study conducted by McConville et al. revealed that colonization with carbapenem-resistant (CR) Enterobacterales (CRE), which is a prerequisite for CRE infection (Kelly et al., 2017), was an independent predictor of 90-day mortality (adjusted odds ratio [OR]: 2.3; 95% confidence interval [CI]: 1.0–5.3; P = 0.056) (McConville et al., 2017). Furthermore, infections caused by CR- or carbapenemase-producing (CP)-GNB were shown to result in high mortality rates (Morata et al., 2012; Poulikakos et al., 2014; Cheng et al., 2015; Micek et al., 2015). This review focuses on global trends, resistance mechanisms, economic burdens, infection control policy and treatment options (including β-lactam combination agents with avibactam, zidebactam, enmetazobactam, relebactam, vaborbactam, nacubactam, durlobactam, and taniborbactam) of CR- and CP-GNB.

The increase in carbapenem resistance in clinically important GNB gradually worsened after 2005, particularly in GNB isolates cultured from patients hospitalized in the intensive care unit (ICU) (Davoudi-Monfared and Khalili, 2018). For example, from 2007 to 2008, Iran reported high imipenem resistance and MDR rates (41.8% and 56.3%, respectively) among P. aeruginosa isolates, especially those carrying class 1 integrons, or those cultured from patients undergoing surgery or hospitalized at the burn unit (Yousefi et al., 2010). Additionally, high MDR/CR rates (> 30%) among HAP-related P. aeruginosa isolates were observed in many member states of the European Union (EU) in the last decade (Micek et al., 2015). In contrast, the MDR rate of Taiwanese P. aeruginosa isolates was less than 18% before 2015. However, the 2016–2018 susceptibility survey of 1,127 P. aeruginosa isolates in Taiwan revealed a trend toward prominent escalation in the annual non-susceptible (NS) rates to anti-pseudomonal carbapenems (from 19.7% in 2016 to 27.5% in 2018 [ Figure 1 ]; 95% CI: 0.545–0.936; P = 0.016) (Jean et al., 2021). When assessed using linear regression analysis, these results corresponded with the annual proportions of pneumonia-causing P. aeruginosa isolates (r = 0.980, P = 0.127) (Jean et al., 2021). An outbreak of XDR-P. aeruginosa infections was reported in a tertiary care pediatric hospital in Italy between 2011 and 2012 (Ciofi Degli Atti et al., 2014). The risk of colonization with CP-P. aeruginosa isolates harboring bla _VIM was also reported to apparently increase with the length of hospital stay (especially > 30-day durations) (Neidhöfer et al., 2021).

After 2005, the isolates of MDR-A. baumannii complex harboring bla _OXA-51 on the ISAba1 element and/or bla _VIM/bla _IMP on the class 1 integron displayed 45%–80% carbapenem resistance rates and were frequently associated with several clusters in the southern states of the EU after 2005 (Kempf and Rolain, 2012). Moreover, the plasmids on Acinetobacter species and some clinical A. baumannii isolates that harbor genetic determinants encoding various carbapenem-hydrolyzing class D β-lactamases (bla _OXA-23, bla _OXA-58, bla _OXA-58-like, bla _OXA-72, etc.) have also been shown to confer high-level resistance to all carbapenem agents in China and Taiwan (Jean et al., 2015). A study conducted at a German hospital by Neidhöfer et al. observed that the bla _OXA-23-encoding A. baumannii complex was more frequently introduced into the hospital by patients residing in the Arabian Peninsula than those of German ethnicity, raising the concern of ethnic factors affecting the infection due to CP-A. baumannii (Neidhöfer et al., 2021). Furthermore, nosocomial infections due to MDR-A. baumannii complex in pediatrics hospitalized at ICU were reported in Turkey (Ozdemir et al., 2011). In contrast to a few Asian countries where an escalating antimicrobial resistance rate was observed among isolates of A. baumannii complex after 2011 (Jean et al., 2013), isolates of A. baumannii complex accounted for solely 2.8% of the implicated organisms among episodes of hospital-acquired pneumonia (HAP) acquired in ICUs in US hospitals between 2015 and 2017 (Sader et al., 2018).

In 2012, a 4.6% colonization rate was reported in a rectal swab CRE survey (utilizing MacConkey agar plate for culture and Xpert MDRO cartridge testing) for patients residing in the nursing homes of Rhode Island, USA (Cunha et al., 2016). In stark contrast, Asia and Africa are two leading continents with the highest global CR prevalence rates among Enterobacterales species (Tilahun et al., 2021). Notably, numerous outbreaks related to CRE involving a wide range of microbial species harboring diverse carbapenemase-encoding genes (bla _KPC, bla _NDM, bla _VIM, bla _OXA, etc.) have been reported in the literature (Chitnis et al., 2012; Kanamori et al., 2017; Mehta and Muscarella, 2020; Tavoschi et al., 2020; De Man et al., 2021). From March 2017 to September 2018, an epidemic spread of CRE, which was rapidly transmitted between hospitalized patients and associated with high mortality rates at 12 Vietnamese hospitals was reported by Tran et al. (Tran et al., 2019). Hospital-acquired infections and carbapenem therapy were determined to be two independent risk factors contributing to CRE colonization (ORs: 1.74 and 1.79, respectively) (Tran et al., 2019). It is noteworthy that CRE infections were also reported among pediatrics with co-morbidities during the last decade in Los Angeles, USA (Pannaraj et al., 2015). Additionally, endoscopy has surprisingly been found to be an under-recognized source of CRE transmission (Mehta and Muscarella, 2020). Consequently, there is a strong need for the utilization of high-level disinfection for cleaning the endoscopic equipment.

An outbreak owing to genetically related KPC-producing K. pneumoniae that persistently existed between March 2009 and February 2011 was reported at one acute care hospital in the USA (Chitnis et al., 2012). In addition, between November 2018 and October 2019, a delayed identification of a cluster involving 1,645 patients who were infected or colonized with NDM-producing CP-Enterobacterales (CPE) was reported in Tuscany, Italy. The majority (accounting for 90.9%) of the implicated CPE isolates that were mostly cultured from the intestinal tract of a total of 1,270 (77.2%) cases were ST147 and bla _NDM-1-harboring CP-K. pneumoniae (Tavoschi et al., 2020).

Stenotrophomonas maltophilia, intrinsically resistant to all carbapenems, is an environmental MDR organism. Although no dominant S. maltophilia clone was identified globally (Kaiser et al., 2009; Duan et al., 2020), it has emerged as an important hospital-acquired pathogen globally (mainly causing primary bacteremia, pneumonia, catheter-associated infection, etc.) among hospitalized patients who receive broad-spectrum antibiotics (especially β-lactams) and/or immunosuppressive agents (Falagas et al., 2009; Brooke, 2012).

Research has revealed that isolates of A. baumannii possess several virulence factors, including pili, outer membrane protein A, lipopolysaccharide capsule, and phospholipase (Richards et al., 2015). Resistance mechanisms of MDR or XDR-A. baumannii complex, listed as one of the critical priority pathogens by experts of the World Health Organization (Tacconelli et al., 2018), usually include paucity of porins, constitutional expression of efflux pumps (AbeABC, AbeFGH, and AbeIJK), and expression of genes encoding various resistance β-lactamases (AmpC cephalosporinase, class B [NDM and VIM] and/or class D [OXA-23, OXA-58-like, etc.] β-lactamases) (Piperaki et al., 2019). High carriage rates of diverse types of OXA enzymes (bla _OXA-51 and bla _OXA-23, followed by bla _OXA-58, bla _OXA-24/40-like, etc.)-encoding genes (77%–100%) have been reported in clinical CR-A. baumannii isolates globally (Chang et al., 2015; Cortivo et al., 2015; Elabd et al., 2015; Lowings et al., 2015; Kateete et al., 2016; Wang T. H. et al., 2018; Ezadi et al., 2020). Furthermore, several acquired insertion sequences or transposons have been determined to promote the overexpression and spread of plasmid-associated bla _OXA-58 genes in Acinetobacter species (Chen et al., 2010; Jean et al., 2015). In contrast to other regions, NDM-encoding genes have been frequently detected in CR-A. baumannii isolates in India (Vijayakumar et al., 2016). They frequently caused ventilator-associated pneumonia (VAP), catheter-associated, and bloodstream infections (BSIs) among debilitated patients hospitalized in the ICU, resulting in > 50% case-fatality rates (Poulikakos et al., 2014; Cheng et al., 2015).

Infections caused by CR/MDR-P aeruginosa are also usually observed in immunocompromised patients (recipients of chemotherapy and/or high-dose corticosteroids), who suffer from pneumonia (Morata et al., 2012) and require mechanical ventilation (Richards et al., 2015). Micek et al. observed that the prevalence rates of MDR phenotypes among P. aeruginosa isolates implicated in HAP in Europe between 2013 and 2014 ranged from 22.2% to 44.2% (Micek et al., 2015). Furthermore, compared to pneumonia due to non-CR/MDR P. aeruginosa isolates, patients with pneumonia caused by CR/MDR-P. aeruginosa had higher lengths of mechanical ventilation (13.1 days vs 17.0 days; P = 0.006) (Micek et al., 2015). The case-fatality rates among patients with pneumonia caused by CR/MDR-P. aeruginosa have been reported to range from 44.7% to 64% (Morata et al., 2012; Micek et al., 2015).

A study conducted by Kao et al., who analyzed the resistance mechanisms in 87 BSI-causing imipenem-resistant P. aeruginosa isolates collected in southern Taiwan between 2000 and 2010, revealed that carbapenemases (mainly VIM and OXA), active efflux pumps, and AmpC β-lactamase overproduction were found in 10.3%, 74.4%, and 51.3% of the P. aeruginosa isolates, respectively (Kao et al., 2016). The prevalence rate of metallo-β-lactamase (VIM, 6.4%) among Taiwanese imipenem-resistant P. aeruginosa isolates was similar to that in another Chinese study (8.5%) (Wang et al., 2010). However, another molecular study that examined CR and XDR-P. aeruginosa isolates (n = 466) collected in Canada between 2007 and 2016 revealed that solely 4.3% (n = 20) harbored a carbapenemase-encoding gene, with Guiana extended-spectrum-5 producers (n = 7 [35%]) surpassing other β-lactamase producers (McCracken et al., 2019). In stark contrast, the 2015–2017 CR-P. A study by Schäfer et al. at three medical centers in Germany revealed that 30.6% (19/62) of the samples harbored either bla _VIM-1 (n = 2) or bla _VIM-2 (n = 17) genes (Schäfer et al., 2019). The bla _VIM carriage rate among CR-P. aeruginosa isolates was similar to that in the 2007–2009 survey conducted in Uganda (32%) (Kateete et al., 2016), and that in the 2015–2016 survey of Dubai hospitals in the United Arab Emirates (32%) (Moubareck et al., 2019). Among worldwide MDR-P. aeruginosa isolates collected in the last decade, clones ST111, ST175, and ST235 have been identified to carry genomic islands (Roy Chowdhury et al., 2017; Yoon and Jeong, 2021). ST235 (producing KPC, and mainly identified in Europe and Asia) and ST111 (producing VIM-2, and mainly identified in all six continents, except Oceania) clones are the most worrisome class A/B carbapenemase-producers of P. aeruginosa, because they are virulent and associated with poor outcomes (Yoon and Jeong, 2021). IMP followed by NDM and VIM have become the two most prevalent class B carbapenemases in worldwide P. aeruginosa isolates (Yoon and Jeong, 2021).

In the BSI-CRE (n=83) study conducted by Tamma et al. at the Johns Hopkins Hospital, USA, between March 2013 and April 2016, 37 (45%) isolates were CP-CRE, of which 92% harbored the bla _KPC-2 gene (Tamma et al., 2017). The CP prevalence rate was highly similar to that reported in a Taiwanese 2017 study (Jean et al., 2018a). In contrast, approximately 90% (121/135) of CRE isolates collected from cancer patients between October 2016 and September 2017 in Egypt, where NDM and OXA-48-like enzymes are prevalent, harbored one or more of the carbapenemase-encoding genes, as revealed by polymerase chain reaction (PCR) (Tawfick et al., 2020). Moreover, PCR analysis of rectal swabs from 590 patients hospitalized in Kuwait between April 2017 and March 2018 revealed that 38 (65.5%) out of the 58 patients (9.8%) with rectal CRE colonization harbored the bla _OXA-181-like gene (combined with bla _KPC-2 [n = 5], bla _VIM-1 [n = 4], and bla _NDM-5 [n = 3]) (Fadhli et al., 2020). Previous studies have revealed that high treatment failure rates are associated with KPC-producing Enterobacterales infections, especially among immunocompromised hosts (Jean et al., 2015; Tawfick et al., 2020). In similarity to invasive infections (bacteremia and pneumonia) that are caused by MDR-P. aeruginosa or MDR-A. baumannii complex resulting in poorer outcomes than those caused by susceptible isolates (Lee et al., 2011; Micek et al., 2015), the all-cause mortality rates related to diverse CRE infections have been notably reported to range from 22% to 72% (Borer et al., 2009; Hirsch and Tam, 2010a; Kalpoe et al., 2012; Tumbarello et al., 2012; Chen H. Y. et al., 2021). Furthermore, a study conducted by Tamma et al. revealed that 32% (12/37) of patients infected with CP-CRE BSIs died within 14 days of admission, with an adjusted OR of 4.92 as compared to non-CP-CRE BSI (Tamma et al., 2017).

The major mechanisms of resistance to carbapenems in S. maltophilia isolates mainly include plasmid-encoding L1/L2 β-lactamases (Avison et al., 2001), and chromosomally encoded MDR efflux pumps (Poole, 2004). High rates of case-fatality (42.6%) and attributable mortality (37.5%) were notably reported in patients with S. maltophilia-causing pneumonia and septicemia, respectively (Falagas et al., 2009; Tseng et al., 2009). Additionally, a Taiwanese study regarding S. maltophilia bacteremia indicated that pediatric patients who had malignancy or failed to remove central venous catheters were at high risk of in-hospital mortality (Wu et al., 2006).

Table 1 presents the prevalence rates of genes encoding carbapenemases among isolates of CRE, CR-Pseudomonas aeruginosa, and CR-A. baumannii in different surveys conducted in different countries. Additionally, Table 2 illustrates the enzymatic and non-enzymatic mechanisms conferring carbapenem resistance among isolates of CRE, CR-P. aeruginosa, and CR-A. baumannii complex.

The huge economic burden caused by MDR-GNB infections, most of which were limited to CRE, has been intensively analyzed. Bartsch et al. investigated the median cost of CRE infections with an incidence of 2.93 per 100,000 persons in the USA in 2015. They estimated that it cost hospitals 275 million US dollars, third-party payers 147 million US dollars, and society 553 million US dollars. In addition, costs increased proportionally with the incidence of CRE, with increases of 2.0-fold, 3.4-fold, and 5.1-fold for incidence rates of 6, 10, and 15 per 100,000 persons, respectively (Bartsch et al., 2017). In-hospital outbreaks of CR- or CP-GNB further exacerbate the already high-cost burden. An outbreak of CPE (caused by mainly NDM-producing K. pneumoniae), which occurred at a London hospital from July 2014 to October 2015, cost €1.1 million, with €54,000 spent on antibiotics for 18 patients who needed treatment, €94,000 on laboratory screening, €153,000 on Estates renovations, and €822,000 as opportunity cost (staff time, bed closure, and elective surgical missed revenue) (Otter et al., 2017). Furthermore, an investigation conducted by Yang et al. at a tertiary teaching hospital in China from 2011 to 2016 revealed that the direct economic burden and disability-adjusted life-year loss caused by BSI due to CR-P. aeruginosa was ≥ 3-fold higher than that of carbapenem-susceptible P. aeruginosa BSI (Yang et al., 2021). According to Semin-Pelletier et al., frequent readmissions of patients who had previous infections due to OXA-48-producing K. pneumoniae isolates, the large number of transfers between wards, and a delay in the implementation of successive cohort units greatly contributed to the incomplete success of containing the spread of CPE (Semin-Pelletier et al., 2015). A few physicians have adopted aggressive surveys of samples from patients to interrupt the transmission of CRE/CPE. For example, a survey at a tertiary teaching hospital in Malaysia revealed that 5.74% of Enterobacterales isolates cultured from various clinical samples (of which rectal swab screening accounted for 49.3%) were CRE, most of which were K. pneumoniae isolates harboring bla _NDM-1 (Zaidah et al., 2017). In the multicenter survey conducted by Jimenez et al. in Miami, Florida from 2012 to 2016, active surveillance testing revealed that the overall CRE prevalence was 0.077 cases per 100 patient-admissions, while the incidence density was 1.46 cases per 10,000 patient-days. It is also noteworthy that rates of CRE (dominated by K. pneumoniae, Enterobacter cloacae, and Escherichia coli) steadily increased during the first 3 years of the study period, and declined after implementation of infection control strategies (contact precautions, environmental disinfection, etc.) (Jimenez et al., 2020).

Owing to the high burden of medical costs and high case-fatality rates seen for inpatients with CPE infections, attempts have been made to improve the cost-effectiveness of screening for CPE among all hospital inpatients (Kang et al., 2020). Among the different culture methods, the ChromID CARBA method (bioMérieux, Marcy l’Etoile, France) has been to perform rapidly and best in the detection of CPE (> 100 colony forming units/spot) from rectal swabs, in terms of sensitivity (92.4%) and specificity (96.9%) (Vrioni et al., 2012; Wilkinson et al., 2012). Despite a lower reagent cost, culture-based methods are, in fact, less sensitive than molecular methods for the detection of infection or colonization of CPE. Moreover, they are labor-intensive and slower to yield results (Richter and Marchaim, 2017). Lapointe-Shaw et al. observed that screening for CPE might be cost-effective as compared to not screening, if the prevalence of CPE was above 0.3% among the isolates of Enterobacterales under survey (Lapointe-Shaw et al., 2017).

Apart from hospital acquired CRE, the presence of CRE in the community setting is also a potentially worrisome threat to the public health of ambulatory patients (Van Duin and Paterson, 2016; Jean et al., 2018b). A meta-analysis conducted by Kelly et al. revealed that 5.6%–10.8% of rates of colonized CRE isolates belonged to the community-associated/community-onset category (CA/CO; defined as identification of asymptomatic CRE colonization at the time of admission) in the USA-based studies, while percentages ranging from 0.04% to 29.5% of colonized CRE categorized as CA/CO in origin were reported globally (Kelly et al., 2017). Compared to healthcare-acquired CRE, a Taiwanese survey conducted by Tang et al. revealed that CA-CRE was more likely to occur in elderly female patients and result in urinary tract infection (UTI) (Tang et al., 2016). In a study conducted in China, Hu et al. also found that CO-CRE isolates (n = 28, accounting for 43.8% of all infection-causing CRE isolates enrolled) were mainly cultured from urine samples (75%). Of the CO-CRE isolates, 8 (28.6%) were clonally unrelated E. coli isolates, all of which were NDM producers that were less resistant to aztreonam, ciprofloxacin, levofloxacin, and chloramphenicol. pneumoniae (Hu et al., 2020).

The emergence of CRE at an LTCF (an institution that provides long-term rehabilitation and skilled nursing care) is also a major healthcare issue (Vrioni et al., 2012). The prevalence and incidence rate of colonized CRE in LTCFs in the USA ranged from 3% to 30.4% (Lin et al., 2013; McKinnell et al., 2019) and 1.07 to 6.83 cases per 10,000 patient-days (Brennan et al., 2014; Chopra et al., 2018), respectively. In contrast, the CRE prevalence rates differed widely among the states of the EU (Chen C.C. et al., 2021). A significant association (ranging from 12% to 15.5%) between CRE colonization in nursing home residents with hospital admissions was observed in Spain (predominantly K. pneumoniae harboring bla _OXA-48-like gene) (Palacios-Baena et al., 2016) and Israel (mainly KPC-producing K. pneumoniae) (Ben-David et al., 2011). Accordingly, nursing home residents have become CRE reservoirs that should not be ignored. Multiple risk factors, including fecal incontinence (OR: 5.78) (Mills et al., 2016), an immunocompromised condition (OR: 3.92), comorbidities (Charlson score > 3; OR: 4.85) (Bhargava et al., 2014), use of gastrointestinal devices (OR: 19.7) (McKinnell et al., 2019), intravascular indwelling devices or urinary catheters (OR: 5.21) (Lin et al., 2013), and mechanical ventilation (OR: 3.56) (Mills et al., 2016), sharing a room with a known CRE carrier (Chitnis et al., 2012), and prior antibiotic exposure (OR: 3.89) (Chitnis et al., 2012; Bhargava et al., 2014; Brennan et al., 2014), etc., has significantly associated with increased vulnerability to CRE colonization and/or infections in LTCF residents. It is noteworthy that patients from LTCFs who were colonized or infected with CRE had notably poor clinical outcomes, with a mortality rate of up to 75% among patients with CRE infection (Borer et al., 2012). In contrast, the prevalence rates of CRE colonization among residents of LTCFs ranged from 13% to 22.7% in Asia (Lee et al., 2017; Hagiya et al., 2018; Jean et al., 2018b; Le et al., 2020). As stated in a survey on the distribution of carbapenemase-encoding genes among LTCF residents (Jean et al., 2015), ST258 CR-K. pneumoniae harboring bla _KPC-2 or bla _KPC-3 were the predominant clones present in residents of LTCFs in the USA, whereas other carbapenemases (including NDM, VIM, IMP, and OXA-48-like) were uncommon among CRE isolates for them (Prasad et al., 2016; Reuben et al., 2017; Dubendris et al., 2020; Chen C.C. et al., 2021). In Japan, various types of IMP (predominantly IMP-42, IMP-11, followed by IMP-6) carbapenemases have been detected among overall CRE isolates in LTCF residents in Japan (Hagiya et al., 2018; Hayakawa et al., 2020). Data from the CRE survey of LTCF residents in Spain revealed that OXA-48-like enzymes, followed by VIM-1, IMP, and KPC are the main carbapenemases that can be found there (Palacios-Baena et al., 2016).

Although P. aeruginosa is not a common colonized GNB cultured from LTCF residents, as reported by the survey conducted by O’Fallon et al. in the USA (O’Fallon et al., 2009), and Italian surveys of Giufrè et al. (Giufrè et al., 2017) and March et al. (March et al., 2017), it has been shown to be easily transmitted through numerous routes, including patient-to-patient contact and environmental contamination (Jefferies et al., 2012). Thus, it is plausible that the CP-P. aeruginosa (harboring bla _VIM) isolates were cultured from LTCF residents who have history of frequent hospitalizations (Nucleo et al., 2018). A study conducted by Raman et al. revealed that MDR/CR-P. aeruginosa can be identified from patients who were transferred from chronic care facilities and exposed to piperacillin-tazobactam (adjusted OR: 2.64) or carbapenem (adjusted OR: 4.36) (Raman et al., 2018).

Table 3 illustrates the summary of CRE, CR-P. aeruginosa, and CR-A. baumannii cultured from the community setting and LTCF.

Early identification of in-hospital patients with risk factors for CRE acquisition (72.7% of which were K. pneumoniae), such as co-colonization with MDR-A. baumannii complex (adjusted OR: 15.6) or ESBL-producing GNB (adjusted OR: 4.7; might be linked to recent carbapenem use), exposure to glycopeptide antibiotics (adjusted OR: 3.6), and admissions within one year (adjusted OR: 3.9), is beneficial for avoiding potential spread (Kang et al., 2019). In addition, excessive consumption of carbapenems (especially group 2 agents) is considered to be an important predisposing factor that contributes to the worsening rates of infections caused by CR-P. aeruginosa (estimated OR: 2.87 - 40.96) (Voor In ’t Holt et al., 2014), CRE (McLaughlin et al., 2013), and CR-A. baumannii complex (Sheng et al., 2010; Yoon et al., 2014). Consequently, appropriate antibiotic control policies (especially strict implementation of antibiotic stewardship) in hospitals, education of primary care staff to prevent the dissemination of high-risk hospital and LTCF microorganisms, and contacting isolation cohorts (Barlam et al., 2016; Hellyer et al., 2016) are of paramount importance in containing the spread of CR- or MDR/XDR-GNB strains and decreasing case-fatality rates. Similarly, there is a need to implement periodical surveillance testing to determine in-time targeted interventions (e.g., isolating or cohorting CRE carriers and nursing staff) are needed to effectively lessen the CRE outbreaks at LTCFs (Ben-David et al., 2011; Chitnis et al., 2012; Chen H. Y. et al., 2021).

The distinguishment of CR-GNB that are due to the non-carbapenemase-mediated mechanisms from CP-GNB is important, because CP-GNB are prone to disseminate between patients more readily than non-CP-GNB (Goodman et al., 2016). Among the phenotypic CRE diagnostic assays commonly used in clinical microbiology laboratories, the modified Hodge test was applied earliest to detect potential KPC producers of CRE. However, it showed poor sensitivity in detection of the NDM and OXA-48-like CPE, and false-positive results are seen in CRE owing to the porin alteration combined with hyperproduction of ESBL and/or AmpC β-lactamase (Tamma and Simner, 2018; Clinical and Laboratory Standards Institute (CLSI), 2021). The Carba NP test and its variants are suitable for detection of various carbapenemases in CRE and CR-P. aeruginosa (Tamma and Simner, 2018). In spite of requiring the acquisition of dedicated reagents and being interpreted subjectively, the Carba NP test is a convenient biochemical test that provides the results within 15-30 minutes and thus has been applied in the clinical microbiological laboratories worldwide (Clinical and Laboratory Standards Institute (CLSI), 2021). Additionally, the CarbAcineto NP test was shown to perform well in detecting carbapenemases produced by CR-A. baumannii (Dortet et al., 2014).

Utilization of the modified carbapenem inactivation method (mCIM) in combination with the EDTA-modified CIM (eCIM) test could reliably differentiate MBL-producing CRE strains (those displaying a negative result on only the eCIM test) from serine-class carbapenemase producers (showing positive results for both tests) (Tamma and Simner, 2018; Jean et al., 2019). Nevertheless, it takes approximately 6-12 h to obtain the results and is interpreted subjectively as well. It is also noteworthy that the mCIM/eCIM test performed less well in detection of VIM-producing P. aeruginosa and OXA-producing A. baumannii isolates than CPE (Tamma and Simner, 2018).

The other carbapenemase detection tests include lateral flow immunoassays (antibody-based rapid diagnostic, easy-to-use methods, such as NG-Test Carba 5 [Hardy Diagnostics, CA, USA], and Resist-3 O.K.N. that detects OXA-48-like, KPC and NDM but not VIM and IMP-like MBLs [Coris BioConcept, Gembloux, Belgium]), targeted carbapenemase assays (inhibitor [phenylboronic acid for KPC and EDTA for MBL]-based, easy-to-use methods) for diverse carbapenemases, and matrix-assisted laser desorption–ionization time of flight mass spectrometry (hydrolysis approach) (Wareham and Abdul Momin, 2017; Tamma and Simner, 2018).

In the present MDR/XDR-GNB era, we have encountered an antibiotic pipeline scenario. Although a few novel antibiotics have been effective in vitro against several CR-GNB, their clinical efficacy requires further validation. The judicious prescription of these valuable antibiotics, strict implementation of antibiotic stewardship policy, adequate disinfection of equipment and environment of hospital and LTCF settings, in combination with in-time screening to initiate necessary cohort isolation, are a few measures that must be vigorously undertaken to lessen the rapidly worsening trends of resistance in clinically important GNBs.

S-SJ and P-RH collected and analyzed the data. S-SJ and DH participated in writing the manuscript. S-SJ, DH, and P-RH read and approved the final version of the manuscript. All authors contributed to the manuscript and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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