ESKAPE Pathogens and Antimicrobial Resistance

ESKAPE pathogens are a group of six bacteria that can cause serious hospital-acquired infections and resist commonly used antibiotics . ESKAPE is an acronym that stands for Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species . These bacteria are Gram-positive or Gram-negative and can be found in the gut flora, soil, water, or other surfaces . They can infect different parts of the body, such as the lungs, blood, urinary tract, or wounds .

ESKAPE pathogens are a major threat to global public health and clinical practice because of their multidrug resistance, which is caused by excessive or inappropriate use of antimicrobials or substandard pharmaceuticals. These bacteria have developed various mechanisms to evade or `escape` the action of different classes of antibiotics, such as β-lactams, glycopeptides, fluoroquinolones, aminoglycosides, macrolides, and others . Some of these mechanisms include antimicrobial inactivation or alteration, antimicrobial target modification, membrane permeability reduction, efflux pumps, and biofilm formation .

Due to these factors, fewer and fewer antibiotic treatments are effective in eradicating ESKAPE pathogens infections, while at the same time there are now no new antibiotics being created due to lack of funding. These ESKAPE pathogens, along with other antibiotic-resistant bacteria, are an interweaved global health threat and are being addressed from a more holistic and One Health perspective .

ESKAPE is an acronym that stands for six highly virulent and antibiotic-resistant bacterial pathogens that cause most of the hospital-acquired infections worldwide. They are:

• Enterococcus faecium: A gram-positive, facultatively anaerobic, lactic acid fermenting, non-hemolytic cocci bacterium that is part of the normal flora of the human gastrointestinal tract. It can cause infections of the bloodstream, urinary tract, surgical wounds, and heart valves. The main concern is the emergence of vancomycin-resistant E. faecium (VRE) strains that are difficult to treat .

• Staphylococcus aureus: A gram-positive, catalase-positive, facultatively anaerobic, cocci bacterium that is the most abundant normal flora of the skin and nasal cavity. It can cause skin and soft tissue infections, food poisoning, urinary tract infections, bacteremia, sepsis, respiratory tract infections, and endocarditis. The most notorious drug-resistant strain of S. aureus is methicillin-resistant S. aureus (MRSA), which is resistant to most β-lactam antibiotics and many other classes of antibiotics .

• Klebsiella pneumoniae: A gram-negative, non-motile, oxidase-negative, rod-shaped bacterium that is part of the normal flora of the human gastrointestinal tract and skin. It can cause pneumonia, especially in patients on ventilators and in intensive care units, as well as urinary tract infections, surgical wound infections, and catheter-associated infections. The major threat is the emergence of carbapenem-resistant K. pneumoniae (CRKP) strains that are resistant to most available antibiotics .

• Acinetobacter baumannii: A gram-negative, aerobic, glucose non-fermenting, coccobacilli bacterium that is normally found in soil and water and as transient flora on human skin. It can cause hospital-acquired pneumonia, especially ventilator-associated pneumonia (VAP), urinary tract infections, wound infections, and bloodstream infections in hospitalized patients. The most dangerous strain of A. baumannii is carbapenem-resistant A. baumannii (CRAB), which is resistant to almost all antibiotics .

• Pseudomonas aeruginosa: A gram-negative, rod-shaped, encapsulated, facultative anaerobic bacterium that is ubiquitous in the environment and can be found on human skin and mucous membranes. It is an opportunistic pathogen that can cause serious infections of the respiratory tract, urinary tract, blood, and wounds in immunocompromised patients. It can also cause infection of burn wounds and outer ears. Multidrug-resistant strains of P. aeruginosa are increasing globally and are resistant to most commonly used antibiotics .

• Enterobacter species: A genus of gram-negative, facultatively anaerobic, lactose-fermenting, rod-shaped bacteria that are part of the normal flora of the human gastrointestinal tract and skin. Enterobacter includes several pathogenic species that mainly cause opportunistic infections in immunocompromised patients. E. aerogenes, E. cloacae, and E. sakazakii are common human pathogens in the genus Enterobacter. They are commonly associated with urinary tract infections and respiratory tract infections. Multidrug-resistant species are resistant to most β-lactams and cephalosporins .

These ESKAPE pathogens have developed various mechanisms to evade or escape the action of different classes of antibiotics, such as antimicrobial inactivation or alteration, antimicrobial target modification, membrane permeability reduction, efflux pumps expression, and biofilm formation. They pose a serious challenge to clinical practice and public health due to their high morbidity and mortality rates .

ESKAPE pathogens are a group of six bacteria that are highly virulent and have increased levels of antimicrobial resistance (AMR), making them extremely challenging to treat. They are the major cause of life-threatening nosocomial or hospital-acquired infections, especially in immunocompromised and critically ill patients . They can evade or `escape` commonly used antibiotics due to their increasing multi-drug resistance (MDR) . They are often isolated from hospital environments and can be spread through contamination of surfaces, equipment, and hands . They can cause infections in various body regions, such as the lungs, blood, urinary tract, and surgical sites .

Some of the common clinical characteristics of ESKAPE pathogens are:

• Enterococcus faecium: It is a gram-positive cocci bacterium that is normally found in the gastrointestinal tract of humans. However, it can cause infections in the bloodstream, heart valves, urinary tract, and surgical wounds. The main concern is the vancomycin-resistant E. faecium (VRE) strains that are resistant to most antibiotics and have high mortality rates.

• Staphylococcus aureus: It is a gram-positive cocci bacterium that is the most abundant normal flora of the skin and nasal cavity. However, it can cause skin infections, food poisoning, pneumonia, bacteremia, endocarditis, osteomyelitis, and toxic shock syndrome. The most notorious strain is the methicillin-resistant S. aureus (MRSA) that is resistant to most β-lactam antibiotics and other classes of antibiotics. MRSA is regarded as a superbug and can cause severe and fatal infections.

• Klebsiella pneumoniae: It is a gram-negative rod-shaped bacterium that is found in the human gut flora and soil. It can cause pneumonia, urinary tract infections, wound infections, septicemia, and meningitis. The most dangerous strain is the carbapenem-resistant K. pneumoniae (CRKP) that is resistant to most antibiotics and has high mortality rates. CRKP can also produce extended-spectrum β-lactamases (ESBLs) that confer resistance to cephalosporins and monobactams.

• Acinetobacter baumannii: It is a gram-negative coccobacillus bacterium that is normally found in soil and water. It can cause pneumonia, urinary tract infections, wound infections, septicemia, and meningitis. It is one of the most difficult bacteria to treat due to its ability to acquire resistance to multiple classes of antibiotics. The most alarming strain is the carbapenem-resistant A. baumannii (CRAB) that is resistant to almost all available antibiotics and has high mortality rates.

• Pseudomonas aeruginosa: It is a gram-negative rod-shaped bacterium that is ubiquitous in soil and water. It is an opportunistic pathogen that can cause infections in the respiratory tract, urinary tract, blood, wounds, and burns. It is also associated with cystic fibrosis and chronic lung infections. It has intrinsic resistance to many antibiotics due to its low membrane permeability and efflux pumps. It can also acquire resistance to other classes of antibiotics through mutations and gene transfer. Multidrug-resistant P. aeruginosa (MDRPA) strains are resistant to most antibiotics and have high mortality rates.

• Enterobacter spp: They are gram-negative rod-shaped bacteria that belong to the Enterobacteriaceae family. They are normally found in the human gut flora and soil. They can cause urinary tract infections, respiratory tract infections, wound infections, septicemia, and meningitis. They can produce ESBLs and AmpC β-lactamases that confer resistance to cephalosporins and β-lactam/β-lactamase inhibitor combinations. They can also develop resistance to carbapenems through mutations or gene transfer.

ESKAPE pathogens are reported globally, mostly in hospital settings. Their prevalence rate is in increasing trend. Due to the lack of a proper surveillance system, no exact data is published (as of 2021), but results published by CDCs in the US and by other European researchers show their prevalence is increasing rapidly .

S. aureus is responsible for the highest number of infections among the ESKAPE pathogens. According to the CDC, in 2017, there were about 323,700 cases of S. aureus infections in hospitalized patients in the US, with 10,600 deaths. MRSA accounted for about 50% of these infections. In Europe, S. aureus was the most common cause of bloodstream infections (BSIs) in 2018, with a proportion of 16.4%. MRSA was detected in 12.3% of S. aureus BSIs.

K. pneumoniae is another major ESKAPE pathogen that causes various types of infections, especially pneumonia and UTIs. In 2017, there were about 168,500 cases of K. pneumoniae infections in hospitalized patients in the US, with 5,400 deaths. CRKP accounted for about 9% of these infections. In Europe, K. pneumoniae was the second most common cause of BSIs in 2018, with a proportion of 14.9%. Carbapenem-resistant K. pneumoniae (CRKP) was detected in 8.3% of K. pneumoniae BSIs.

E. faecium is a Gram-positive ESKAPE pathogen that causes mainly BSIs and surgical site infections (SSIs). In 2017, there were about 80,500 cases of E. faecium infections in hospitalized patients in the US, with 5,400 deaths. VRE accounted for about 80% of these infections. In Europe, E. faecium was the third most common cause of BSIs in 2018, with a proportion of 10.4%. VRE was detected in 15.9% of E. faecium BSIs.

A. baumannii is a Gram-negative ESKAPE pathogen that causes mainly pneumonia and wound infections. In 2017, there were about 8,500 cases of A. baumannii infections in hospitalized patients in the US, with 700 deaths. CRAB accounted for about 63% of these infections. In Europe, A. baumannii was the seventh most common cause of BSIs in 2018, with a proportion of 2.9%. CRAB was detected in 63% of A. baumannii BSIs.

P. aeruginosa is a Gram-negative ESKAPE pathogen that causes various types of infections, especially pneumonia and wound infections. In 2017, there were about 51,500 cases of P. aeruginosa infections in hospitalized patients in the US, with 2,700 deaths. Multidrug-resistant P. aeruginosa accounted for about 13% of these infections. In Europe, P. aeruginosa was the fifth most common cause of BSIs in 2018, with a proportion of 7%. Multidrug-resistant P. aeruginosa was detected in 15% of P. aeruginosa BSIs.

Enterobacter spp. are Gram-negative ESKAPE pathogens that cause mainly UTIs and RTIs. In 2017, there were about 197,400 cases of Enterobacter spp. infections in hospitalized patients in the US, with 2,000 deaths. Multidrug-resistant Enterobacter spp. accounted for about 12% of these infections. In Europe, Enterobacter spp. were the fourth most common cause of BSIs in 2018, with a proportion of 9%. Multidrug-resistant Enterobacter spp. were detected in 10% of Enterobacter spp. BSIs.

ESKAPE pathogens are responsible for a significant burden of morbidity and mortality worldwide and pose serious challenges for infection prevention and control measures.

ESKAPE pathogens are multi-drug resistant (resistant to more than three classes of antibiotics). They are resistant to most of the antibiotics that were traditionally used to treat these bacteria. Some of the most common resistant antibiotics and the most serious strains of ESKAPE pathogens are listed in the table below.

ESKAPE pathogens have developed several resistance mechanisms to escape the action of different classes of antibiotics. Some of the most common mechanisms are:

• Antimicrobial Inactivation or Alteration: The production of enzymes that irreversibly destroy or modify the antimicrobial molecules resulting in their inactivation or alteration. For example, β-lactamases that hydrolyze the β-lactam ring of penicillins and cephalosporins; and aminoglycoside modifying enzymes that modify the amino or hydroxyl groups of aminoglycosides.
• Antimicrobials’ Target Modification: Modifying the antibiotic target sites to reduce the affinity of antibiotic molecules to bind with the bacterial components. For example, modification of penicillin binding proteins (PBPs) that reduce the binding of β-lactams; and methylation of ribosomal RNA that reduce the binding of macrolides and linezolid.
• Modification in Membrane Permeability: Reducing the membrane permeability to decrease the uptake of antibiotics. For example, modification or loss of porin channels that reduce the entry of β-lactams and fluoroquinolones.
• Efflux Pumps: Extruding the intracellular antibiotics out of the bacterial cells. For example, RND type efflux pumps that expel multiple classes of antibiotics such as β-lactams, aminoglycosides, fluoroquinolones and macrolides.
• Biofilm Formation: Forming a protective layer of extracellular matrix that restricts the penetration and action of antibiotics. For example, biofilm formation by S. aureus and P. aeruginosa on medical devices and wounds.

ESKAPE pathogens have developed several resistance mechanisms to escape the action of different classes of antibiotics. Some of the most common mechanisms are:

• Antimicrobial Inactivation or Alteration: The production of enzymes that irreversibly destroy or modify the antimicrobial molecules resulting in their inactivation or alteration, is the most common antimicrobial resistant (AMR) mechanism. The Gram-negative bacteria in the ESKAPE group (Pseudomonas, Acinetobacter, Klebsiella, Enterobacter) produce enzymes that destroy active sites of the antimicrobials or modify the main structural components of the antimicrobial. For example, β-Lactamases enzyme production is the main AMR mechanism in Gram-negative ESKAPE pathogens. These enzymes confer resistance against the β-Lactam antibiotics by hydrolyzing the β-Lactam ring of the antibiotics . Aminoglycoside Modifying Enzymes (AMEs) are another example of enzymes that covalently catalyze the modification of specific amino groups or hydroxyl groups of aminoglycosides and reduce their affinity to bind with bacterial ribosomes .

• Antimicrobials’ Target Modification: Modifying the antibiotic target sites is another common AMR mechanism in ESKAPE pathogens to prevent themselves from the deleterious effect of antibiotics. Modifying the target sites reduces the affinity of antibiotic molecules to bind with the bacterial components. Bacteria can modify target proteins, enzymes, ribosomes, cell wall components, nucleic acid binding sites, etc., to develop resistance against antibiotics. For example, bacteria modify Penicillin Binding Proteins (PBPs), which are the target site of the β-Lactams . Similarly, modification in DNA gyrase and Topoisomerase IV enzymes helps bacteria to prevent themselves from the action of quinolones . Methylation of specific residues of 23S rRNA and 16S rRNA confers resistance against macrolides, lincosamide, streptogramin, linezolid and aminoglycosides . Modification in cell-wall precursors is one of the most important AMR mechanisms in S. aureus and E. faecium which provides resistance against glycopeptides .

• Modification in Membrane Permeability: Reduction in membrane permeability causes a reduction in uptake of antibiotics; hence the concentration of intracellular antibiotics will be low resulting decrease in the action of antibiotics. One of the main mechanisms to reduce membrane permeability is a modification in porins or down-regulation or loss of porins channels in the outer membrane. Modification in porins contributes to resistance to β-Lactams and fluoroquinolones, which are porin dependent on penetrating the bacterial cells. It is a major AMR mechanism in carbapenem resistance Acinetobacter baumannii and Pseudomonas aeruginosa .

• Efflux Pumps: Efflux pumps that extrude intracellular antibiotics contribute greatly to the AMR mechanism. There are six classes of efflux pumps in bacteria related to AMR, and all of these are found in ESKAPE pathogens; they are resistance-nodulation-division (RND), major facilitator superfamily (MFS), multidrug and toxic compound extrusion (MATE), small multidrug resistance (SMR), ATP-binding cassette (ABC), and proteobacterial antimicrobial compound efflux (PACE). Most of these efflux pumps are responsible for effusing different types of antibiotics rather than those in a single category . RND type efflux pump plays a major role in conferring multi-drug resistance to Gram-negative ESKAPE pathogens. They expel not only antibiotics but also dyes and detergents .

• Biofilm Formation by ESKAPE Pathogens: Biofilm formation is an important phenomenon demonstrated mainly by S. aureus, P. aeruginosa, A. baumannii, and K. pneumoniae among the ESKAPE pathogens. Biofilm not only increases the chances of survival in medical devices (or inanimate surfaces) but also provides resistance to antibiotics . Biofilm increases resistance against antibiotics by restricting antibiotic penetration, modifying antibiotics, increasing interaction between different bacterial species, upregulating effluxes, enhancing horizontal gene transfer, etc. .

WHO, CDC, and ECDC have listed ESKAPE pathogens under urgent and serious threat lists and have prioritized their surveillance, research, and focus on them. A major focus is research and development of new effective antimicrobials, antimicrobial stewardship, and prevention of hospital-acquired infections (HIAs).

There is limited treatment option left to fight against ESKAPE pathogens. Besides the treatment mentioned above (in the table), several drugs are under research (as of 2020) and trials; like combination therapy, silver nano-particle therapy, phage therapy, and new antibiotics like plazomicin, cefiderocol, meropenem – vaborbactam, imipenem + cilastatin + relebactam, sulbactam – durlobactam, ceftobiprole, tebipenem – pivoxil, lascufloxacin, etc.

Some of the most promising therapeutics for the treatment of the ESKAPE-related biofilms are antimicrobial peptides, bacteriophages, bacteriophage-encoded products, and natural products such as essential oils (EOs) to eradicate them.

Targeting ESKAPE pathogens with anti-infective medicinal plants from the Greater Mpigi region in Uganda is another approach that has been explored by some researchers. They identified 16 medicinal plant species used by traditional healers for the treatment of infectious and inflammatory diseases and evaluated their ability to inhibit growth of clinical isolates of multidrug-resistant ESKAPE pathogens. They found that extracts of Zanthoxylum chalybeum and Harungana madagascariensis stem bark showed potent antibacterial activity against S. aureus and E. faecium, while extracts of Solanum aculeastrum root bark and Sesamum calycinum subsp. angustifolium leaves exhibited strong quorum sensing inhibition activity against all S. aureus accessory gene regulator (agr) alleles.

These are some of the examples of the works being done against ESKAPE pathogens. However, more research and investment are needed to develop novel and effective strategies to combat these dangerous pathogens.

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