One of the primary reasons for the emergence of antibiotic resistance (AMR) worldwide is over-the-counter availability of antibiotics. With the incidences rising alarmingly, AMR poses severe challenges to the general public and the medical fraternity. AMR accounts for a significant proportion of the global morbidity and mortality rates associated with bacterial infections. The most important contributor to multi-drug resistance (MDR) is Gram-negative bacteria. Recently, MDR focus has been placed on Carbapenem-resistant Gram-negative bacteria. The World Health Organization (WHO) lists CRE, Carbapenem-resistant Acinetobacter baumannii (CRAB), and Carbapenem-resistant Pseudomonas aeruginosa (CRPA) as priority AMR pathogens that pose significant threats to human health [1].

Enterobacterales are Gram-negative facultative anaerobes that cause a broad spectrum of severe infections such as septicemia, community/hospital/ventilator-acquired infections, complex urinary tract infections (cUTIs), and intra-abdominal infections ^[2][3][4][2,3,4]. Because of the wide range of infections caused by this group of bacteria, AMR due to these bacteria has a significant effect at the socio-economic and public health levels. Carbapenem is widely used to treat infections caused by extended-spectrum b-lactamase (ESBL)-producing Enterobacterales. Widespread use of Carbapenem against these organisms has led to the emergence of carbapenemase-producing Enterobacterales (CPE), whose infections are challenging to treat with the other drug [5]. Carbapenem acts by inhibiting peptidoglycan synthesis by inhibiting the transpeptidases. The CRE develops resistance to Carbapenem by either producing carbapenemase enzyme that digests the Carbapenem or the acquired structural mutations that induce the production of other β-lactamases [6].

Carbapenem is an antibiotic against severe bacterial infections, although often reserved for MDR bacterial infections. It is a β lactam antibiotic that works like penicillin and cephalosporins, which belong to the same class. Carbapenem exerts its antibiotic effects by inhibiting transpeptidases, thereby inhibiting peptidoglycan synthesis. Inhibition of peptidoglycan synthesis in the Gram-negative bacteria causes the cells to undergo lysis [6]. The Gram-negative CRE has developed resistance to the carbapenems. The resistance offered by CREs against Carbapenem is usually caused by either hydrolysis of the antibiotic by carbapenemase they produce or structural mutations that induce expression of other β-lactamases including AmpC cephalosporinase and ESBL ^[7][8][7,8]. Carbapenemase are usually categorised into one of three classes: Class-A Klebsiella pneumoniae carbapenemase (KPC), Class-B metallo-β-lactamases (MBLs), and Class-D oxacillinases (OXA)-type enzymes. The enzymes from different classes exhibit differential inhibitory effects on carbapenem. The beta-lactamases are further classified into 4 classes (Figure 1).

Class B carbapenemases, also called Metallo beta-lactamases (MBLs), have at least one zinc ion to break down the beta-lactam ring. Class A and D carbapenemases have a serine amino acid at their active site. Klebsiella pneumoniae carbapenemase (KPC) is the most frequently detected Class A carbapenemase, and it is currently the most common in the United States [6]. Penicillins, cephalosporins, carbapenems, and aztreonam (ATM) may all be hydrolyzed by them, and clavulanic acid can partly block them. Although they may also be found in non-fermenters Gram-negative bacteria, they are more often seen in Enterobacterales. This category includes carbapenemases such as Serratia marcescens enzyme (SME), imipenem-hydrolyzing beta-lactamase, non-metallo-carbapenemase of class A (NMC-A), and Guyana extended-spectrum beta-lactamase (GES). But aztreonam and ion chelators such as ethylenediaminetetraacetic acid (EDTA) or dipicolinic acid (DPA) block class B carbapenemases, which helps treat or identify these microorganisms [7].

Additionally, when no additional resistance mechanisms are exhibited, MBLs are resistant to beta-lactamase inhibitors but remain susceptible to ATM. The Verona integron-encoded MBL (VIM), the New Delhi MBL (NDM), and imipenemase are some of the MBLs with the greatest clinical significance. Due to the many sequence variants that have been discovered within this group, class D carbapenemases (sometimes referred to as oxacillinases or OXAs) comprise the largest class of carbapenemases. Class D carbapenemases differ from class A and class B in that they are resistant to beta-lactamase inhibitors and EDTA, have only modest hydrolytic activity against carbapenemases, and have no impact on extended-spectrum cephalosporins. The majority of Class D carbapenemases have been discovered in Acinetobacter spp., in particular, OXA-51, which is chromosomally expressed in Acinetobacter baumannii and may confer carbapenem resistance. Notably, although they are found in Acinetobacter spp., OXA-48-like enzymes are the only subgroup with an actual prevalence in the Enterobacterales ^[6][8][6,8].

The growing use of carbapenem has caused more selection for CRE genes, consequently accelerating the emergence of CRE [9]. The rise in the prevalence of CRE worldwide, with limited treatment options available, has made the situation worse. Polymyxins (colistin or polymyxin B) and tigecycline have been the drugs of choice since the beginning to treat CRE infections [10]. However, resistance against these antibiotics is increasing steadily. Fosfomycin and aminoglycosides are the other antibiotics used occasionally to treat CRE infections ^[3][4][11][3,4,11]. When treating CRE infections of lower minimum inhibitory concentration (MIC), carbapenems remain the treatment of choice but have to be used in high doses or as part of combined-drug therapy.

However, there are concerns about the effectiveness, adverse effects, and increasing resistance against these antibiotics [12]. Some CRE-infected patients have shown resistance to colistin [13]. The colistin-resistant genes (mcr 1-5) carried on the plasmids are transferable between bacteria, thereby spreading the colistin resistance ^{[14][15][16][17][18][19]}[14,15,16,17,18,19]. The European Medicines Agency recently authorised the use of a new antibiotic combination (ceftazidime-avibactam) in treating complicated infections, HAP, and those resulting from aerobic Gram-negative bacteria [3]. There is inadequate confirmation of the results, and there are high chances of developing resistance [3].

Combination therapy serves the purpose in treating several complex infectious diseases. Combination therapy has been shown to increase the efficacy of treatment, but it also increases the side effects as well as the probability of death ^[20][21][20,21]. Specific combination therapies have been approved, including meropenem-vaborbactam and imipenem-relebactam, while others are still in development, such as aztreonam-avibactam [3]. There are additional agents approved recently and used for CRE, such as plazomicin, cefiderocol, and eravacycline ^[3][20][3,20]. Therefore, for CRE infections, combination therapies/combinations of antimicrobial agents were tested by several groups both in vivo and in vitro and have been shown to have survival benefits ^[21][22][21,22]. However, these studies do not provide reliable evidence because of variations in research design as well as mechanisms of resistance. Figure 2 summarises the therapeutic options for CRE infections.

The carbapenem resistance is carried out by the genes present on the plasmids of the bacteria. These genes encode for β-lactamases [23]. The carbapenemase enzymes hydrolyse all β-lactam antibiotics, thereby conferring carbapenem resistance to the bacteria. The Enterobacterales carry the resistance genes on their plasmids that express the most important carbapenemases, i.e., KPC and the New Delhi Metallo-β-lactamase (NDM). KPC has been widely reported in the United States, southern Europe, Israel, and China, while NDM has been reported in northern Europe, the UK, and India ^[24][25][26][24,25,26]. KPC is the commonest of all the carbapenemases globally, followed by NDM [27]. The third most common carbapenemase worldwide is the OXA-48-type oxacillinase. It has been reported mostly in North Africa and Europe. Verona integron-encoded and imipenemase metallo-β-lactamases (VIM and IMP) are the two other metallo-β-lactamase carbapenemase like NDM. They share a similar mechanism of transmission of resistance, although they are rarer.

From a U.S. study conducted in 2016, 48 states reported the presence of CRE resulting from KPC, 25 states reported NDM, 19 states reported OXA-48, and 6 states reported VIM [28]. Currently, there is no efficient treatment for CRE as they are resistant to almost all the antibiotics available. Colistin is one of the antibiotics used against CRE, but recent reports have documented colistin resistance among CRE ^[29][30][29,30]. The very first report of colistin-resistant CRE came from the U.S. The mcr-1 gene present conferred the resistance on the plasmid [31].