The spread of resistant bacteria has caused serious concern worldwide. The spread of Multidrug-Resistant (MDR) bacteria limits the choice of antibiotics, making those available less effective. Such bacterial infections increase morbidity and mortality, lengthen hospital stays, and increase healthcare expenses. Nosocomial pathogenic microorganisms, known as ESKAPE pathogens exhibit multidrug resistance and increased levels of pathogenicity. These pathogens are associated with high morbidity, mortality, and prolonged hospital stays, posing a serious threat to public health. The rapid emergence and spread of Multidrug Resistant (MDR) strains have outpaced the development of new antibiotics, challenging treatment strategies and infection control measures. Addressing the threat of ESKAPE pathogens requires a multifaceted approach involving antimicrobial stewardship, stringent infection prevention practices, rapid diagnostics, and innovative therapeutic alternatives. The aim of this paper is to review antibiotic resistance in ESKAPE pathogens.

• ESKAPE Pathogens; Antimicrobial Resistance; Multidrug Resistance; Antibiotics; Bacteria

Tesfaye E, Tesfaye K, Diriba A, Bachiru D, Jobir G (2025) Antibiotic Resistance in ESKAPE Pathogens: A Growing Challenge to Global Health. Ann Clin Pathol 12(2): 1181.

Antimicrobial Resistance (AMR) poses a threat to the efficient prevention and management of a growing number of infections brought on by bacteria, parasites, viruses, and fungi. Of all AMR pathogens, antibiotic-resistant pathogens are associated with the highest burden and medical expenses [1]. The extensive use of antibiotics in medicine, agriculture, and food production, as well as environmental factors and the density of the microbial population, all contribute to the complicated natural process of antibiotic resistance [2]. It is thought to have emerged due to the misuse and overuse of various antibacterial agents in both the health care and agricultural industries. AMR is also influenced by spontaneous evolution, bacterial mutation, and the transmission of resistant genes via horizontal gene transfer [3].

The spread of AMR jeopardizes decades of medical advancement in the twenty-first century and poses a threat to the security of public health worldwide. Low- and middle-income countries (LMICs) bear a disproportionate amount of the cost of this complex issue, which results in high rates of morbidity and mortality [4]. By 2050, it is predicted that AMR, a silent pandemic, will have killed over 40 million people. The World Health Organization (WHO) estimates that AMR directly caused 1.27 million deaths globally in 2019 and contributed to 4.95 million deaths overall. The rising incidence of antibiotic-resistant infections, especially those contracted in hospitals, is a major burden on healthcare systems worldwide [5,6]. There are substantial financial expenses associated with AMR in addition to death and disability. According to World Bank estimates, AMR may lead to one trillion dollars in additional healthcare expenses by 2050 and one trillion to 3.4 trillion dollars in annual Gross Domestic Product (GDP) losses by 2030 [7].

ESKAPE pathogens are groups of Gram-positive (Enterococcus faecium and Staphylococcus aureus) and Gram-negative (Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species) bacteria. They are the leading cause of potentially fatal nosocomial infections in critically ill and immunocompromised patients [8]. They are the most popular bacteria in health care settings and known for developing high levels of antibiotic resistance via different mechanisms [9]. The ESKAPE group is distinguished by pathogenic, transmission and resistance traits, which are represented by enzyme inactivation, target change, cell permeability alteration through porin loss or by increasing the expression of efflux pumps, and mechanical protection through biofilm synthesis [10].

Globally, infections related to ESKAPE pathogens are the principal cause of morbidity, mortality, and economic burden. They are considered a leading cause of nosocomial infections, posing significant challenges in clinical practice. ESKAPE pathogens were among organisms listed as antibiotic resistant bacteria [11,12]. A comprehensive, cross-cutting approach is required to address the emergence of antibiotic-resistant bacteria, a significant public health risk. MDR infections, in particular “ESKAPE” bacteria, can tolerate lethal doses of antibiotics with a wide range of chemical compositions and modes of action [13]. WHO listed ESKAPE bacteria as one of the priority bacterial pathogens having a major global public health challenge [14]. The “ESKAPE” group of pathogens requires the greatest attention from a clinical and research and development standpoint due to their total mortality and economic burden [15].

Enterococcus faecium

A Gram-positive, facultative anaerobic Enterococcus known as Enterococcus faecium is frequently found as commensals in the colon, throat, mouth, and vagina. It is one of the enterococci species that is harmful to humans and has virulence genes associated with blood, intra-abdominal, skin, and soft tissue infections, as well as infections of the urinary system, pelvis and endocarditis, particularly in immunocompromised and hospitalized patients. Due to its growing antibiotic resistance and capacity to cause serious infections with its virulence genes, these bacteria, which causes nosocomial infections, is clinically significant [16,17]. Furthermore, E. faecium generates virulence factors that contribute to its persistence in clinical and environmental settings, including cytolysin, aggregation substance, hyaluronidase, gelatinase, and enterococcal surface protein (encoded by the cyl, asa, hyl, gel, and esp genes) [18].

The rise of Vancomycin-Resistant Enterococci (VRE) has raised concerns globally and presented treatment issues due to the scarcity of accessible antibiotics. Vancomycin resistance in enterococci is primarily mediated by the acquisition of vanA and vanB gene clusters, which alter the target site of vancomycin by modifying the terminal dipeptides of peptidoglycan precursors from D-Ala-D-Ala to D-Ala-D-Lac or, less commonly, D-Ala-D-Ser, thereby reducing the drug’s binding affinity [19]. Despite the identification of vancomycin resistance genes (vanA, vanB, vanC, vanD, vanE, vanG, vanM, and vanL), the most prevalent in VREfm are vanA, which is linked to resistance to both vancomycin and Teicoplanin, and vanB, which is linked to resistance to vancomycin but not Teicoplanin. Mobile genetic elements that carry these dominant genes include the transposons Tn1546 and Tn1549/Tn5382, which are linked to vanA and vanB, respectively [20].

Vancomycin-resistant E. faecium (VREfm) is the primary cause of infections associated with healthcare. A study done in a Nepalese hospital to characterize ESKAPE bacteria revealed that vancomycin-resistant E. faecium accounted for 20%. According to this study, resistance to other antibiotics such as ciprofloxacin (92%), gentamicin (52%), tetracycline (48%), tigecycline (48.0%), and Teicoplanin (12%) was also detected. On the other hand, molecular characterization showed that vancomycin resistant E. faecium harbored the vanA and vanB genes [21]. Another study conducted in China revealed the prevalence of E. faecium to be 92.5%. According to this study, all the isolates (100%) were resistant to ampicillin while 62.5% of them were resistant to nitrofurantoin. In addition, 65.0% and 12.5% of the isolates carried predominantly esp and hyl genes, respectively [22].

In addition to vancomycin, aminoglycoside-resistant E. faecium was also found. A study carried out in Northwest Iron revealed the presence of the van gene in 57.1% of the VRE isolates, of which 47.6% had the vanA gene. In addition, aminoglycoside resistance genes (ARG) were also detected. Resistance genes like ant (3“)-III (78%), followed by aph (3’)-IIIa (67%), ant (6’)Ia (62%) and aac (6’)-Ie-aph (2”) Ia (15%) were the most prevalent ARG. The frequencies of aph (2″)-Ib and ant (4′)-Ia were 7 and 4%, respectively [23]. Due to the production of Aminoglycoside Modifying Enzymes (AME), which render aminoglycosides inactive, the emergence of High Level Aminoglycoside Resistant (HLAR) enterococci has presented serious challenges for infection management [24].

One of the drugs used to treat MDR Gram-positive bacteria, including VRE is linezolid. The most prevalent mechanism granting enterococci resistance to linezolid is mutations in the 23S rRNA gene, which are known to arise during linezolid therapy. Despite the fact that 23S rRNA mutations cause the majority of clinical LRE strains, transferable genes that confer linezolid resistance are becoming more widely known and described. These include genes that encode the ribosomal protection proteins OptrA and PoxtA, as well as genes that encode the Cfr family proteins (cfr, cfr(B), and cfr(D)), which bind to and catalyze the methylation of the adenine nucleotide at position 2503 (A2503) of the 23S rRNA [25]. Several studies revealed that two genes, optraA and poxtA, are responsible for the emergence of Linezolid resistant E. faecium (LRE). Studies done in France, Ireland and Czech Republic showed that LRE isolates accounted for 0.2%, 7.8%, and 13.4% [26-28]. Another study that involved molecular analysis revealed that linezolid resistance in E. faecium was also attributable to the cfr(D) gene [29].

Staphylococcus aureus

Staphylococcus aureus is Gram-positive cocci, a facultative anaerobe, catalase-positive, and coagulase positive bacteria. It is a common bacterial flora that colonizes human skin and mucous membrane. This bacterium can also be found in both community and healthcare settings. It causes a diverse range of infections, including pneumonia, sepsis, infective endocarditis, toxic shock syndrome, and necrotizing fasciitis [30]. S. aureus is among ESKAPE pathogens that can cause severe illness and express resistance to multiple antimicrobial agents. It has emerged as one of the main important human pathogens and a leading cause of hospital- and community-acquired infections [31]. Bacterial virulence and host variables can affect the severity of a S. aureus infection, which can happen once the skin or mucous membranes’ barrier breaks down [32].

Several studies revealed that the most common and prevalent strain is Methicillin-Resistant S. aureus (MRSA). MRSA is a strain of S. aureus known to resist most beta lactam antibiotics, including methicillin, penicillin, oxacillin, and amoxicillin. This resistance results from the presence of the mecA or mecC gene, which codes for a modified penicillin-binding protein (PBP2a or PBP2c) that decreases the antibiotics’ potency [33]. It is a major clinical problem in hospitals and a leading cause of death globally [34]. Most nations in the world have reported genetically diverse MRSA lineages, some of which were characterized by global outbreaks and others with limited geographic distributions [35].

MRSA infections rank second in attributable mortality among all drug-resistant bacteria. The increasing prevalence MRSA has significant financial and medical system consequences. Due to continuous strain evolution, antibiotic iteration and updates, as well as increased migration frequencies among different regions, MRSA infections have become more complex and diverse, presenting new challenges to the management of MRSA infections [36]. MRSA infections increase rates of morbidity and mortality, lengthen hospital stays, and increase treatment costs, further taxing already limited healthcare resources. Patients with MRSA typically stay for six to fourteen days, which is excessive and raises the expense of treatment. Furthermore, increased morbidity increases societal costs and affects patients’ productivity [37]. The limited treatment options and potential for spread among healthcare facilities, communities, and other settings make the rising prevalence of MRSA infections a serious public health concern [38]. Methicillin resistance in S. aureus is not restricted only to hospital settings, but also in individuals in the human community. Methicillin resistance of S. aureus in hospital settings causes hospital associated MRSA (HA-MRSA) while in community it is responsible for what is termed community acquired MRSA (CA-MRSA). Recently, livestock associated MRSA (LA-MRSA) has also been widely reported among several species of animals including pigs, poultry and cows. The ability of S. aureus to colonize various host species makes it an increasingly recognized as zoonotic pathogen [39]. Nowadays, S. aureus has shown resistance against many antibiotics globally. Resistances to penicillin, methicillin, vancomycin, fluoroquinolones, Oxazolidinones, macrolides, Lincosamides, Streptogramins, aminoglycosides, tetracyclines and chloramphenicol are the most prominent and have become a global health threat. The following table shows the resistances and their mechanism (Table 1).

Table 1: Mechanism of Resistance in S. aureus in different antibiotics.

Klebsiella pneumoniae

Klebsiella pneumoniae is a Gram-negative opportunistic pathogen that causes infections in humans. It is one of the clinically relevant organisms that have caused considerable public health concerns. It is also one of the opportunistic infections that causes a wide range of disorders and increasingly frequently develops antibiotic resistance. The ability of K. pneumoniae to resist the majority of the commonly used last-line antibiotics is quickly becoming well known. It produces a variety of acute infections, which makes it particularly dangerous in hospitals [62].

K. pneumoniae is a common nosocomial pathogen that presents serious therapeutic issues due to its exceptional capacity to build resistance to several medicines. Pneumonia, urinary tract infections, bloodstream infections, wound or surgical site infections, and meningitis are among the worst illnesses linked to K. pneumoniae in healthcare settings. It is highly common bacterium responsible for nosocomial infections, especially in critically ill patients in the intensive care unit (ICU) [63]. K. pneumoniae develops antibiotic resistance through a variety of processes, including the frequent horizontal transfer of antibiotic resistance genes and the enhancement of antibiotic resistance through biofilm formation [64]. This bacterium resists antibiotic action via enzymatic inactivation and modification, antibiotic target inactivation, porin loss and mutation, efflux pump expression, and biofilm formation [65].

Several strains of K. pneumoniae have developed a wide range of β-lactamase enzymes recently, which can break down the chemical structure of β-lactam antibiotics such as penicillin, cephalosporins, and carbapenems. One of the main ways that K. pneumoniae resists antibiotics is by producing different beta-lactamase enzymes. Common beta-lactamases identified in K. pneumoniae include TEM, SHV, and CTX-M kinds, with some strains additionally producing carbapenemases like KPC [66].

The percentage of K. pneumoniae isolates that are resistant to carbapenem has grown with the introduction of the super enzyme known as New Delhi metallo-β lactamase (NDM-1) and encoded by blaNDM-1. Its capacity to neutralize carbapenems makes it a hazard to other antibiotics, including aminoglycosides, fluoroquinolones, and β-lactams [67]. Efflux pumps and the development of biofilms are other mechanisms of resistance in K. pneumoniae [68,69]. The following summarizes overview of the underlying mechanisms attributed to antibiotic resistance in K. pneumoniae (Table 2).

Table 2: Summary of resistance mechanisms in K. pneumoniae and related genes.

Acinetobacter baumannii

Acinetobacter baumannii is a Gram-negative, non motile, catalase positive, oxidase negative coccobacillus associated with hospital-acquired infections worldwide. The most common infections caused A. baumannii are pneumonia associated with ventilation and central-line associated infections in bloodstream. A. baumannii can survive extreme unfavorable conditions because of its ability to form biofilms, resist desiccation, its pathogenic properties and surface adhesions. MDR has been found in 45% of the strains of this lethal opportunistic pathogen [87].

Acinetobacter baumannii is regarded as a difficult pathogen and a serious epidemiological threat because of its propensity to acquire resistance to several antimicrobial drugs and to infect hospitalized patients. Because it can survive in a hospital setting and is known to cause difficult to-treat infections, such as bloodstream infections, wound infections, and severe Ventilator-Associated Bacterial Pneumoniae (VABP), which affect patients who frequently already have other serious medical conditions, this bacterium has grown in importance in healthcare settings, especially intensive care units (ICUs) [88]. It is a clinically problematic Gram-negative species that causes bacteremia, especially in healthcare settings, with an estimated mortality risk ranging from 20 to 39% [89].

Acinetobacter baumannii is a pathogen of special concern. It is a “difficult-to-treat” bacterium that causes infections with mortality rates as high as 60% (via community-acquired pneumonia) and 43.4% (through bloodstream infections). According to the most recent WHO list, A. baumannii is still a top priority, and the CDC has classified it as a “Urgent” concern [90]. A. baumannii’s success as a pathogen is attributed to a variety of factors, including its capacity to elude immune responses, withstand desiccation, withstand disinfectants, and build biofilms on surfaces and medical devices [91].Acinetobacter’s remarkable genetic flexibility is one of its most potent weapons, enabling quick genetic changes and rearrangements as well as the incorporation of foreign determinants transported by mobile genetic elements. Among these, insertion sequences are thought to be one of the main factors influencing the evolution of bacteria and their genomes. Furthermore, A. baumannii has the ability to create biofilms, which extends its survival on medical equipment like ventilators in ICUs [92]. The most common way that antibiotic resistance genes are acquired in A. baumannii is by a variety of Mobile Genetic Elements (MGEs), including as integrons, Insertion Sequences (ISs), Transposons (Tns), Genomic Islands (GIs), and Plasmids [93]. A. baumannii isolates develop resistance in a number of methods, such as by the enzymatic breakdown of antibiotics, target site alteration, changed membrane permeability, multidrug efflux pumps, and the production of biofilms [94].

Pseudomonas aeruginosa

Pseudomonas aeruginosa is a gram-negative bacteria belonging to the Pseudomonadaceae family. It is obligate aerobic, motile, and aerobic non-spore forming bacteria. It is opportunistic pathogenic bacterium, extensively distributed in nature and harmful to people, plants, and animals [113]. It is widely distributed in a variety of niches, including soil, water, and vegetation. It’s regarded as one of the most opportunistic organisms that can cause nosocomial infections in clinical settings, such as septicemia, pneumonia, wound infections, and urinary tract infections [114]. Both humans and animals can contract acute and chronic infections from this opportunistic pathogen. P. aeruginosa causes nosocomial infections in humans, especially in immunocompromised patients who have life-threatening conditions and injuries in the Intensive Care Unit (ICU) [115].

Because of its extensive natural habitat distribution and noteworthy toxicity in the medical field, P. aeruginosa has garnered a lot of interest. Its capacity to induce persistent infections in hosts is significantly aided by its exceptional adaptability to a wide range of ecological niches and habitats. The main reason for its adaptability and pathogenic versatility is its big genome, which has a sophisticated regulatory network that enables it to react to many environmental stressors in an efficient manner [116]. Because it can endure a range of physical circumstances and survive with little food, it can endure in both community and hospital settings. Hospital infections mainly affect patients in intensive care units, as well as those who have burns, catheterizations, or long-term medical conditions [117,118].

The rising incidence of Multidrug-Resistant (MDR) Pseudomonas aeruginosa is a major global public health concern. P. aeruginosa isolates frequently exhibit intrinsic, mutational, and horizontally acquired resistance to antibiotics, which may significantly reduce the range of treatment options for severe P. aeruginosa infections [119]. P. aeruginosa pathogenic arsenal includes a variety of virulence factors that boost the microorganism’s competitiveness by neutralizing human defenses, causing tissue damage, and forming biofilms. Flagella, fimbriae, superficial polysaccharides, and pili-type IV are additional significant virulence factors in P. aeruginosa that contribute to bacterial colonization [120]. Furthermore, P. aeruginosa has an outer membrane rich in lipopolysaccharides that envelops the bacterial cell and blocks the entry of several antimicrobials, making it naturally resistant to a number of frequently used in clinical practices [121,122]. This picture is also influenced by other elements, including the generation of antimicrobial-inactivating enzymes, the efflux system (which actively drives the antibiotics out of the cell), and the outer membrane’s poor permeability [123]. The following table summarizes summary of the general mechanism of resistance related to P. aeruginosa (Table 3).

Table 3: Mechanism of resistance in A. baumannii against different antibiotics.

Enterobacter species

Enterobacter species are Gram-negative, aerobic, motile and non-fastidious bacteria that belong to the family of Enterobacteriaceae. Enterobacter cloacae and Enterobacter aerogenes are included in the Enterobacter Cloacae Complex (ECC) and are capable of producing different infections. Due to its greater genotypic similarities with the genus Klebsiella, E. aerogenes was reclassified as Klebsiella aerogenes in 2019 [140]. At present, the genus Enterobacter comprises 23 species [141]. Identifying the ECC at the species level is essential for related studies. ECC is categorized using genomic parameters such as Average Nucleotide Identity (ANI) and Digitalized Dna Dna Hybridization (dDDH), in addition to strain-to-strain phylogenetic congruence Enterobacter Cloacae Complex (ECC) members are nearly universal in nature and have the ability to cause disease [142,143]. Generally, studies have indicated that the genus Enterobacter has a complicated and dynamic taxonomy that includes numerous distinct species, subspecies, and species complexes [144]. Enterobacter species are responsible for a large number of nosocomial and community-acquired infections, such as respiratory, soft-tissue, urinary tract, bloodstream infections, osteomyelitis, and endocarditis infections [145,146]. Enterobacter species, as one of the members of the ESKAPE bacteria, are a major contributor to worse health outcomes and higher treatment expenses [147].

Multi-Drug Resistant (MDR) ECC strains have arisen and spread globally as a result of the extensive use of antibiotics; ECC infections account for 65–75% of ESKAPE Pathogens Infections [148]. Because ECC isolates display intrinsic AmpC β-lactamases, such as CMH, ACT, and MIR with numerous variations, they are inherently resistant to ampicillin, amoxicillin–clavulanate, and first and second generation cephalosporins. Antibiotic overuse has led to the emergence and global spread of Multidrug Resistant (MDR) ECC Strains [149]. Overproduction of AmpC is typically linked to resistance to the majority of third-generation cephalosporins. Additionally, resistance to third-generation cephalosporins is caused by the acquisition of genes encoding Extended Spectrum β-lactamase (ESBL) [150,151]. MDR strain infections typically lead to increased mortality, lengthier hospital stays, and higher expenses, which has a significant effect on public health worldwide [152].

One of the major challenges in managing infections caused by Enterobacter spp. is their capacity to produce Extended Spectrum β-lactamases (ESBLs) and carbapenemases, which confer resistance to multiple antimicrobial agents. Furthermore, these resistance genes are often located on MDR plasmids containing additional resistance genes, including aminoglycoside and fluoroquinolones resistance genes [153]. ECC has emerged as the third most prevalent Enterobacteriaceae bacterium implicated in hospital-acquired infections globally due to the spread of carbapenemases and ESBLs [154]. Currently, Carbapenem-Resistant Enterobacter Cloacae Complex (CRECC) emergence and spread have grown to be serious public health issues. CRECC strains can be widespread in healthcare institutions and often have several drug resistance genes. The primary mechanism of carbapenem resistance in ECC is the synthesis of carbapenemases, among which KPC, NDM, IMP, and VIM are the most common, with KPC dominating [155]. Carbapenem resistance is also caused by the overexpression of efflux pumps, the synthesis of ESBLs or AmpC, and a decrease in the expression of Outer Membrane Proteins (OMPs) [156]. MDR strains of ECC bacteria can colonize high-contact surfaces in ICU, where exposure to many clinically prescribed broad-spectrum antibiotics is likely. Colonized ECC bacteria have the potential to cause nosocomial infections in susceptible patient populations in hospitals with inadequate infection control procedures. The widespread use of broad-spectrum antibiotics may encourage the selection and colonization of MDR ECC in human guts, particularly in low- and middle-income nations [157,158]. Numerous causes of acquired and intrinsic antimicrobial resistance have reduced the number of viable treatments available for ECC infections [159]. The following table summarizes resistance mechanisms in ECC against common antibiotic (Table 4 and Table 5).

Table 4: Resistance mechanism in P. aeruginosa to common antibiotics.

Table 5: Mechanism of resistance in Enterobacter cloacae complex.

Nosocomial infections due to ESKAPE pathogens have been on the rise in both developed and developing nations. One of the significant clinical difficulties and a growing area of concern resulting from these infections is AMR [176]. The ESKAPE bugs have developed the capacity to eliminate every other antimicrobial delivery strategy. In addition, they can undergo rapid mutagenesis, which helps them generate resistance against antimicrobials [177]. Antibiotic resistance has prompted scientists to look for a secure and powerful antibiotic substitute. One of these alternatives is the use of phages. Particularly in light of the growing prevalence of AMR, phage therapy, which employs lytic bacteriophages to infect and eliminate harmful bacteria, presents a possible substitute for conventional antibiotics [178]. When the bacteriophage enters the target bacteria, the bacterial synthetic machinery is redirected to the production of viral genomes and proteins. Then, after assembly and packaging, cells will be lysed, resulting in the release of new virions that can infect other bacterial cells. The advantages of phages are their specificity, which enables them to kill only the pathogens that they can recognize. Another advantage of phages is safety. They are safer due to their ability to replicate only in target bacteria without infecting host cells [179,180].

Combination therapy is another way of combating the bad bugs with no drugs, ESKAPE pathogens. Combination therapy increases membrane permeability, reduces efflux pump activity, and inhibits intrinsic antibiotic resistance [181]. One such notable combination is the use of non beta lactam beta lactamase inhibitors such as avibactam, relebactam, tazobactam, zidebactam and vaborbactam. These are able to augment the activity of beta lactams in the absence of beta lactamase. Most common combinations are ceftazidime/avibactam, Ceftozolane/tazobactam, imipenem/relebactam, meropenem/vaborbactam and cefepime/zidebactam [182]. Due to its synergistic effect and wider coverage of susceptible microorganisms, combination antimicrobial therapy has emerged as a viable therapeutic option for infections brought on by bacteria that are MDR. Nevertheless, there is a chance that this treatment will lead to increasing toxicity and the emergence of multidrug resistance [183].

Finding anti-resistance medications is an essential step towards regaining the antibacterial efficacy of currently available antibiotics against multidrug resistant pathogens. These medications could either prevent common bacterial resistance mechanisms or boost an antibiotic’s antimicrobial effects. One of these notable anti-resistance drugs is beta-lactamase inhibitors and efflux pump inhibitors. Common beta-lactamase inhibitors include clavulanic acids, penicillin-based sulfones, diazabicyclooctanes (DBOs) and boronic acids. Common efflux pump inhibitors are phenylalanine arginyl β-naphthylamide and pyranopyridine [184].

Quorum Sensing (QS), cell-to-cell communication process in biofilm, is common in bacteria, especially MDR ESKAPE pathogens. Thus, QS is thought to be a possible target for the creation of novel, non-antibiotic anti-biofilm agents. Inhibitors of QS can block the QS process, which is a key stage in the development of bacterial pathogenicity [185]. Another method of fighting bacteria in biofilm is application of Photodynamic Inactivation (PDI). A method called photodynamic PDI was developed as an alternative therapy to get rid of microorganisms and bacteria that are resistant to several drugs in planktonic cultures and biofilms. The lethal action of PDI is dependent on the generation of Reactive Oxygen Species (ROS) by the stimulation of a photosensitizer with visible light under aerobic conditions [186].

Recently, nano-based technology has been identified as a promising technology for combating antimicrobial resistance, including resistance related to ESKAPE pathogens. Application of nanotechnology provides accurate testing and therapies for MDR ESKAPE pathogens. This technology utilizes nanoparticles, which are made at a size of nanometers. They are extremely small, have a large surface area and are highly reactive nature [187]. The improvement of these nanoparticles over current antibiotics is their capacity to limit drug degradation, increase drug accumulation at the target sites and reduce toxicity. Nanoparticles are used as delivery systems for delivering antibiotic to its target site in MDR bacteria and also kill the agent by themselves. Nanotechnology is also important in molecular imaging and biomarker detection as a means to provide accurate detection of resistant genes in MDR ESKAPE pathogens [188]. Furthermore, there are numerous innovative strategies being researched to reduce the impact of AMR, including Fecal Microbiota Transplantation (FMT), medicine repurposing, Monoclonal Antibody (MAb) therapy, and vaccine development [189].

Rapidly increasing spread of drug resistant bacteria, including ESKAPE bacteria and their transmissible infections is now a global challenge. The number of antibiotics used to treat ESKAPE bacteria has gradually decreased over time, while only a few of new antibiotics or antibiotic combinations have been added to the arsenal. AMR infections, in contrast to infections that are quickly treated with antibiotics, lengthen hospital stays and generate instability in the healthcare system by necessitating expensive and time-consuming therapies [190].

Antibiotic misuse promotes the development of germs that are resistant to them and poses a growing danger to our ability to treat bacterial infections. The development and spread of drug-resistant bacteria worldwide is also a result of poor agricultural practices, the routine use of antibiotics to livestock without prescription, and environmental variables. Antibiotic-resistant bacterial infections raise morbidity and mortality, burden the healthcare system with high expenses, result in significant economic losses, and are anticipated to overtake all other causes of death [191,192]. By focusing on the ESKAPE species, we can more effectively address the widespread problem of antibiotic resistance, particularly MDR. AMR problems require multi-sectoral collective efforts at different levels [193]. Priorities peculiar to each country must be considered in national AMR plans. These strategies should concentrate on establishing human and veterinary infection-control programs, enhancing human and animal health surveillance for resistant microorganisms, conducting research on novel diagnostic and therapeutic approaches, and implementing educational initiatives aimed at the public and professional groups [194].

Studies have shown that ESKAPE pathogens are the leading cause of HAIs with high resistance patterns to numerous antibiotics currently in use. AMR and HAIs are global health challenges in both developed and developing countries. A brake has to be put on the rapidly increasing spread of these pathogens with their resistant nature, especially in developing countries. Infection prevention activities and the judicious use of antibiotics are priority issues that have to be strengthened. Studies on the prevalence of antibiotic-resistant bacteria, including ESKAPE pathogens in developing countries are limited and inconsistent. Therefore, further research on the burden of these pathogens should be conducted, followed by appropriate utilization and implementation of the findings, and strict follow-up an important recommendation.

Conceptualization: ET. All authors actively participated in this review.

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