Antimicrobial resistance (AMR) is now a global concern. Furthermore, the global and rapid spread of multi-drug-resistant (MDR), extensively drug resistant (XDR) and pan-drug resistant bacteria (known as superbugs), which cannot be treated using the current antimicrobials and other drugs that we have in our arsenal is frightening as even common infections can become life-threatening to living populations.

The ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are critical not only because they cause the majority of nosocomial infections, but also because they represent transmission, pathogenesis, and resistance paradigms [1]. The ESKAPE microorganisms are included in the list of “high priority pathogens” of the World Health Organization (WHO) “pathogen priority list,” with the most critical sub-group corresponding to MDR bacteria that cause a particular threat in hospitals. Some of these bacteria include A. baumannii, P. aeruginosa, and Enterobacter spp. The second tier in the list—the “high priority category”—contains E. faecium and S. aureus [2].

Over the last decade, A. baumannii and P. aeruginosa have risen to the top of the list of community-acquired infections [[3], [4]]. Overall, the most prevalent P. aeruginosa infections in India were reported as being urinary tract infections (UTIs), wound infections, and bloodstream infections [5]. K. pneumoniae bacterial cells are part of the normal human intestinal flora but they become dangerous when they invade other body compartments, causing respiratory-, urinary tract- and bloodstream infections. They constitute the most common pathogenic bacteria isolated in nosocomial infections due to their expression of numerous virulence factors and antibiotic resistance genes [6]. K. pneumoniae is now under strict monitoring because intestinal isolates can cause serious illnesses and their resistance to last-resort treatment (carbapenem antibiotics) has now spread worldwide. In India, K. pneumoniae strains are usually isolated from respiratory-, urinary tract-, wounds, and bloodstream infections [[7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31]]. Enterobacter spp. are responsible for many nosocomial infections such as UTIs, respiratory-, soft tissue infections, osteomyelitis, and endocarditis. They are also frequently associated with post-lung transplant pneumonia, being transmitted to the transplanted patients by the contaminated transplant [32]. E. faecium are Gram-positive cocci of the normal human intestinal flora, but they are also known to cause nosocomial infections such as bacteraemia, UTIs, or endocarditis. Resistance to these dangerous hospital-acquired pathogens was recently reported to be on the rise in India [33]. S. aureus Gram-positive cocci constitute a significant cause of nosocomial infections worldwide. In India, S. aureus isolates are mainly detected in infected wounds and bloodstream infections. They were recently described as antibiotic-resistant in India, the USA and Europe, yet at a higher level in India than in the developed world [34].

To date, more than 1000 antibiotic molecules have been identified. However, only a limited number of these molecules are used in routine to treat human bacterial infections. These belong to 1) cell wall synthesis inhibitors, which include β-lactam pharmacophores such as penicillins, cephalosporins, monobactams and carbapenems. In addition to β-lactams, glycopeptides, lipoglycopeptides and polymyxins are also parts of the antibiotic families that target bacterial cell wall synthesis; 2) the protein synthesis inhibitors, which include aminoglycosides, macrolides, tetracyclines, lincosamides, streptogramins, chloramphenicol and oxazolidinones; 3) the RNA synthesis inhibitors rifampicin and rifamycin; 4) the DNA replication inhibiting fluoroquinolones (such as ciprofloxacin) and 5) the folate synthesis inhibitors sulfonamides (such as sulfasalazine or sulfamethoxazole) and trimethoprim [35].

AMR is known to arise following mutations in endogenous chromosomal genes and/or as the result of horizontal gene transfer (HGT) during which bacteria acquire resistance gene(s) carried by a plasmid, a transposon, or an integron [36]. Among all the various antibiotic classes currently in use, β-lactams count among the most commonly used [37]. Unfortunately, numerous bacterial species now express β-lactamases that inactivate β-lactam antibiotics by hydrolysing the peptide bond of the characteristic 4-atom β-lactam ring. These dynamic enzymes have an extended spectrum of substrates and are referred to as Extended Spectrum β-lactamases (ESBL) [38]. According to the Ambler's classification, which is based on β-lactamases structural homologies, 4 classes of β-lactamases can be distinguished: 3 of them contain a serine residue in their active site while the fourth one refers to metallo-β-lactamases (MBLs) that contain a metallic ion in their active site (B group of β-lactamases). Most of these MBLs are encoded by blaVIM, blaIMP, and blaNDM-1 genes. Group A of β-lactamases consists in penicillinases, carbapenemases, and ESBLs encoded by many different variants, the most prevalent ones being blaTEM, blaSHV, blaCTX−M, and KPCC. This last gene is specific to K. pneumoniae. Group C of β-lactamases consists in cephalosporinases encoded mainly by the chromosomal gene AmpC while group D of β-lactamases consists in oxacillinases encoded by blaOXA genes [39]. The genes encoding these β-lactamases are mostly carried out by a plasmid acquired by HGT. Importantly, at this point, while β-lactamases of the A-C-D groups can be inhibited by an inhibitor of β-lactamases such as clavulanate, sulbactam or tazobactam co-administered with the β−lactam antibiotic [40], no inhibitor of the MBL group B of β-lactamases has been reported so far, except for EDTA, when used in vitro. EDTA is however impractical to inhibit in vivo MBL β-lactamase activities, which are nevertheless the most concerning ones in the developing world. Despite the recent and global rise of non-MBL cabapenemases, no promising β-lactamase inhibitor has been identified yet.

As in other regions of the world, India currently uses many and large doses of antibiotics, the most broadly used molecules being those included in our study. Furthermore, although AMR genes are found naturally in the environment, the lack of rapid diagnostic methods identifying ESKAPE pathogens and AMR genes in Indian clinical settings has resulted in the overuse of broad-spectrum antibiotics leading to an increase in the development of AMR [41]. The ability of ESKAPE pathogens to acquire and disseminate various resistance genes by HGT sustained this MDR. The emergence of pathogens that no longer respond to antibiotics, making infections harder to treat and increasing the risk of lethal disease spread, has been paralleled by a waning antibiotic development pipeline.

Based on numerous surveillance studies, the American Centers for Disease Control and Prevention (CDC), the European Centre for Disease Prevention and Control (ECDC), and the WHO provide regular quantitative information regarding the status of AMR in ESKAPE pathogens in the USA and Europe. Massive surveillance data are also available in China. By contrast, except for the Indian Council of Medical Research (ICMR) AMR surveillance network report in 2018 [42], at the moment, there is no such systematic monitoring of AMR in India [43], where the infectious disease burden is yet among the highest in the world.

We analysed here the data collected during an extensive literature survey of the 2010–20 decade on the antibiotic resistance trends in these ESKAPE pathogens in India supported by the prevalence of β-lactamase activities and genes. India is currently the world most populous country (1 428 627 663 inhabitants in India in 2023) and the seventh-largest country by land area (total of 3 287 263 km2). The studied time period was divided into two sub-periods to facilitate the task of tracking the spread of antimicrobial resistance. The results highlighted a notable increase in the resistance rates to antimicrobial agents over the 2010–20 decade and demonstrated that there is an urgent need for health care measures to be taken in order to take control on the antimicrobial resistance spread and avoid extensive suffering and mass succumbing to infections that used to be successfully cured.