ESKAPE Pathogens

ESKAPE is the acronym for six nosocomial pathogens that can ‘escape’ commonly used antibiotics due to their increasing multi-drug resistance (MDR). These pathogens are; Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.

These are a list of pathogens that possess the highest risk of developing resistance to multiple drugs. The WHO published the lists of pathogens carrying the highest risk of developing multi-drug resistance in 2017 among. This group (ESKAPE) was classified under the status of priority.

ESKAPE bacteria are susceptible to many genetic mutations. Due to this, they have developed resistance to lipopeptides, 𝛽-lactams, tetracyclines, fluoroquinolones, macrolides, and many antibiotics. These antibiotics are the last line in the defense. 

Enterococcus faecium

• E. faecium is a gram-positive coccus found in environmental components like soil, water, and plant. 
• It is a normal flora of human and animal digestive organs and is also used as probiotics.
• Because of its opportunistic nature of infection and its ability to resist the antibiotic naturally and develop resistance. Later on, it is capable of causing severe nephrotoxicity that leads to septicemia in humans.
• E. faecium is usually associated with nosocomial infections.
• This bacteria has developed resistance to vancomycin, erythromycin, glycopeptides, tetracycline, aminoglycosides, gentamicin, and streptomycin. Vancomycin resistance Enterococcus faecium is the top area of concern.

Staphylococcus aureus

• S. aureus is gram-positive cocci, usually seen in grape-like clusters.
• It is the normal flora of the skin and nose but can cause skin infections (wounds), pneumonia, osteomyelitis, food poisoning, sepsis, and toxic shock syndrome.
• In recent years, Staphylococcus has been associated with resistance to different penicillin classes, shifting the use of vancomycin and teicoplanin as first-line antibiotics in treating their infection.
• These can also form biofilms in health care settings creating difficulty in treatment with antibiotics.

Klebsiella pneumoniae 

• K. pneumoniae belongs to the Enterobacteriaceae family.
• These are non-fastidious, capsulated gram-negative rod-shaped bacteria. 
• These bacteria are capable of causing lower respiratory infections and urinary tract infections in catheterized patients.
• These bacteria can produce beta-lactamases, which have helped the bacteria develop resistance to penicillin and ampicillin.
• Similarly, some strains of Klebsiella can produce an enzyme, extended-spectrum beta-lactamases increasing the resistance to multiple drugs such as cephalosporin or ceftazidime.
• In the last five years, Klebsiella pneumoniae has been capable of producing carbapenemases (KPCs).
• Carbapenemases can destroy the carbapenems increasing the bacteria’s resistance to an even more comprehensive range.  
• Efflux pumps, porins, and biofilms are also why bacteria develop resistance to antimicrobial agents.

Acinetobacter baumannii

• Acinetobacter baumannii is gram-negative coccobacillus.
• It is found in environmental components and is an opportunistic pathogen causing nosocomial infections, especially in ICU patients.
• The infections caused by these bacteria are pneumonia, bacteremia, urinary tract infections, meningitis, and wound infections. 
• These bacteria are resistant to antibiotics like 𝛽- lactam, and carbapenem due to production of carbapenemase, metallo- 𝛽-lactamases, and oxacillinase serine 𝛽- lactamases
• Multidrug resistance isolates of MDR have RND efflux pumps helping the bacteria gain resistance to a broad range of antibiotics, like tetracycline, macrolides/lincosamides, chloramphenicol, and aminoglycosides.

Pseudomonas aeruginosa

• Gram-negative rod-shaped facultative anaerobic bacteria.
• It is a normal flora of the gut and an opportunistic pathogen in immunocompromised populations.
• Exogenous source like contact with the environment is the cause of infection. 
• Pseudomonas aeruginosa develop resistance to imipenem due to change in porin.
• It also develops resistance to carbapenems, fluoroquinolones, and aminoglycosides due to the presence of RND efflux pumps.

Enterobacter species

• Gram-negative rod-shaped bacteria.
• They belong to the family Enterobacteriaceae.
• The two main species of the family is Enterobacter cloacae, and Enterobacter aerogenes (now named Klebsiella aerogenes).
• These are opportunistic, and infections are usually seen in immunocompromised hospitalized patients.
• These have a wide range of mechanisms for antibiotic resistance. Many produce KPC, ESBLs, and metallo beta lactamase.
• The MDR strains of Enterobacter are resistant to almost all antimicrobial agents except tigecycline and colistin.

Importance of ESKAPE Pathogens Clinically

• They carry the utmost chance of developing MDR.
• As most of the infections caused by these pathogens are hospital-acquired and resistant to most antimicrobial agents, a cure for these in recent years may not be available.

How Do these Bacteria Develop Resistance?

The Capability of Modifying Sites of Drug Binding

• Some bacteria develop resistance to antimicrobial agents by modifying the target site of the agents. One example is methicillin-resistant Staphylococcus aureus (MRSA) which expresses a unique PBP2a (penicillin-binding protein) with less affinity towards 𝛽-lactam antibiotics giving the MRSA bacteria to survive in the presence of 𝛽-lactam antibiotics including methicilin. 
• Similarly, glycopeptide antibiotics target gram-positive bacteria’s cell wall component (peptidoglycan). Some genes (VAN-A, VAN-B, VAN-C, VAN-D, VAN-E, and VAN-G) of Enterococcus faecium can change the peptidoglycan crosslink increasing resistance to glycopeptide antibiotics. 

The Ability to Transfer the Resistant Gene

Studies have shown that Enterococci species can transfer their vancomycin-resistant gene to other bacteria like Staphylococcus aureus, which has led to the generation of vancomycin-intermediate Staphylococcus aureus (VISA) and vancomycin-resistant S. aureus (VRSA).

The Haphazard Use of Antibiotics

Continuous and unsupervised use of antibiotics helps the bacteria develop resistance to different antibiotics. Antibiotics are the best weapon for fighting against bacterial infections, so the rational use of antimicrobial drugs by strengthening antimicrobial stewardship programs is necessary.

Reduction in Accumulation of Intracellular Drugs

One of the mechanisms of susceptibility of bacteria to antibiotics is the balance of uptake and release of the drug. Some bacteria can reduce the uptake of antibiotics through cell membranes leading to developing resistance to those antibiotics. Bacteria achieve this by decreasing protein channels on the outer membrane and the presence of an efflux pump to decrease the amount of accumulating drugs in the cell.

Loss of Porin

This mechanism is seen in gram-negative bacteria. The bacteria can lose proteins in the outer membrane called porins (responsible for forming channels for the passage of hydrophilic substances like antibiotics) from its membrane. Bacteria like Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae exhibit resistance to imipenem, meropenem, and 𝛽-lactams antibiotics, respectively.

Efflux pump

• Some bacteria do the removal of antibiotics from inside the cell by proteins found in the membrane, functioning as exporters (efflux pumps). The pumps excrete the drug from the cell at a higher rate creating an antibacterial effect; most of these pumps can efflux out multiple drugs creating multidrug resistance. 
• Poly-selective efflux pump is the most common the resistance-nodulation-division (RND) family found in MDR isolates of Gram-negative bacteria like Pseudomonas aeruginosa. 
• Other bacteria like A. baumannii, E. aerogenes, and K. pneumoniae have also increased in producing these efflux pumps. 

Biofilm Production

• The matrix of biofilm is the significant reason for bacteria to develop antimicrobial resistance instead of other reasons. Because the matrix provides a mechanical and biochemical shield to decrease the activity of drugs.
• S aureus, P aeruginosa, A baumannii, and K pneumoniae makes biofilms in health care sectors .

References:

• Navidinia, M. (2016). The clinical importance of emerging ESKAPE pathogens in nosocomial infections. Archives Of Advances In Biosciences, 7(3), 43-57. https://doi.org/10.22037/jps.v7i3.12584
• Santajit, S., & Indrawattana, N. (2016). Mechanisms of Antimicrobial Resistance in ESKAPE Pathogens. Biomed Research International, 2016, 1-8. https://doi.org/10.1155/2016/2475067
• Nichols, H. (2022). MRSA: Treatment, causes, and symptoms. Medicalnewstoday.com. Retrieved 19 May 2022, from https://www.medicalnewstoday.com/articles/10634.