MDR multi-drug resistance pathogens are a global problem and hospital wide resistance pathogens is a growing concern and there is a greater risk for nosocomial infection by such pathogens so what are ESKAPE pathogens? E : Enterococcus Faecium It is a gram positive bacteria, related to genus Enterococcus. S : Staphylococcus aureus Gram Positive bacteria usually found in the nose and the skin of healthy people. Methicilline resistance from of staph aureus or known as MRSA is increasing and it is one of hard to treat infections. Linezolid and vancomycin are used to treat MRSA.

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Open in a separate window —: no classification in Ambler system. Chromosomally encoded AmpC are usually identified in P. Ambler class D consists of a variety of enzymes, such as oxacillin hydrolyzing enzymes OXA. Furthermore, OXA-type carbapenemases are commonly found in Acinetobacter spp.

Specific A. Modification of Drug Binding Sites Some resistant bacteria avoid recognition by antimicrobial agents by modifying their target sites.

The mutation of gene encoding for penicillin-binding proteins PBPs , which are enzymes typically anchored on the cytoplasmic membrane of the bacterial cell wall and function in assembly and control of the latter stages of the cell wall building, results in the expression of unique penicillin-binding proteins, for example, the expression of a unique PBP2a in S.

Bacterial cell wall synthesis in methicillin-resistant Gram-positive organisms can be inhibited by glycopeptides, which target acyl-D-alanyl-D-alanine acyl D-Ala-D-Ala residues of peptidoglycan precursors. Reduced Intracellular Drug Accumulation The balance of antibiotic uptake and elimination determines the susceptibility of bacteria to a particular drug. Thus, reducing the amount of antibiotic able to pass through the bacterial cell membrane is one strategy used by bacteria to develop antibiotic resistance.

Porin Loss The outer membranes of Gram-negative bacteria contain proteins called porins that form channels that allow the passage of many hydrophilic substances, including antibiotics. A reduction in the amount of P. Multiple-drug resistant K. Efflux Pumps To increase the removal of antibiotics from the intracellular compartment or the intermembrane space in Gram-negative bacteria , some bacteria contain membrane proteins that function as exporters, called efflux pumps, for certain antimicrobial agents.

These pumps expel the drug from the cell at a high rate, meaning that the drug concentrations are never sufficiently high to elicit an antibacterial effect. Most efflux pumps are multidrug transporters that efficiently pump a wide range of antibiotics, contributing to multidrug resistance. Up to date, there are five super families of efflux pumps that have been described. These include the ATP-binding cassette ABC family, the small multidrug resistance family, the major facilitator super family, the resistance-nodulation-division RND family, and the multidrug and toxic compound extrusion family [ 25 ].

The most common type of efflux pump in Gram-negative bacteria is the polyselective efflux pump, belonging to the RND superfamily, which plays a key role in the multidrug resistance MDR bacterial phenotype. This type of pump expels a variety of antibiotics and structurally unrelated molecules, such as dyes and bile salts, but also detergents and biocides that are frequently used in medical practice [ 26 ].

They are usually chromosomally encoded. These two efflux pumps are essential for bacterial survival, particularly in the presence of toxic agents. Two of these efflux pumps, MexAB-OprM and MexCD-OprJ, are responsible for resistance to at least three main classes of antibiotics, namely, carbapenems, fluoroquinolones, and aminoglycosides [ 27 , 28 ].

Furthermore, many clinical P. An increase in the prevalence of strains overproducing these efflux pumps has also been reported in Enterobacter aerogenes and K. Overexpression of the AcrAB efflux pump, together with decreased expression of porins, is characteristic of imipenem-resistant E. In these bacteria, the efflux pump also ejects other unrelated antibiotics, such as fluoroquinolones, tetracycline, and chloramphenicol.

Like P. Finally, the synergistic effect of multidrug efflux pumps and the outer membrane barrier is important for resistance to many agents. For example, the main porin expressed by P. Biofilm Formation Biofilms are complex microbial communities living as a thin layer on biotic or abiotic surfaces, implanted in a matrix of extracellular polymeric substances created by the biofilms themselves.

Microorganisms within the biofilm can interact with each other, as well as the environment. The major component of the matrix is secreted extracellular polymeric substances, mainly consisting of polysaccharides, proteins, lipids, and extracellular DNA from the microbes [ 29 ]. There are three key steps for biofilm formation. The first step is adhesion, which occurs as cells reach a surface and anchor to the site.

The second step is growth and maturation, which happens as the microbes begin to generate the exopolysaccharide that establishes the matrix and then mature from microcolonies to multilayered cell bunches. The final step is detachment, which can be divided into two types: active and passive. Active detachment is initiated by bacteria themselves, for example, by quorum sensing and enzymatic degradation of the biofilm matrix.

In contrast, passive detachment is caused by external forces, such as fluid shear, scraping, and human intervention [ 30 ]. It could be argued that the main causes of antimicrobial resistance are not classical drug resistance mechanisms, that is, efflux pumps, target site modification, or enzymatic degradation. It is likely that the matrix of biofilms provides a mechanical and biochemical shield that provides the conditions needed to attenuate the activity of the drugs e.

Under these conditions it is difficult to eliminate bacteria using conventional antibiotics. Moreover, when the bacteria experience nutrient scarcity, they could become tolerant to antibiotics. This may explain the apparent greater antibiotic resistance of cells in the deep layers of a biofilm bacteria extracted from the biofilms and grown in broth recover their full susceptibility, indicating that the resistance is phenotypic and not genotypic [ 31 ].

The most common pathogens found in biofilms in a healthcare setting are S. Enterococcus faecium Enterococcus species were formerly classified as part of the genus Streptococcus. They are Gram-positive facultative anaerobes, which are often found in pairs or chains. Their normal habitat is the gut of humans and animals. There are more than 20 Enterococcus species, but Enterococcus faecium and Enterococcus faecalis are the most clinically relevant.

Most Enterococcus infections are endogenously acquired, but cross-infection may occur in hospitalized patients [ 33 ]. Over the past decade, some reports have revealed a rise in ampicillin- and vancomycin-resistant enterococcal infections in healthcare facilities. For instance, in Netherlands, the average number of invasive ampicillin-resistant enterococcal infections in university hospitals escalated from approximately 10 infections in to 50 infections in per hospital [ 34 ].

Rates of antimicrobial resistance amongst enterococci are particularly concerning, especially the incidence of vancomycin-resistant Enterococcus VRE , which is mainly associated with E.

Despite the high global rates of VRE, there is some geographical variation. In , Galloway-Pena and her colleagues demonstrated two diverse clades of E.

Clade A clinical isolates were found to associate predominantly with hospitals, whereas clade B isolates were associated with community origin.

In addition, clade A has acquired several virulence determinants and resistance genes from the presence of insertion sequence 16 IS16 and a gene encoding the ampicillin-resistant PBP5 pbp5R while clade B has been shown to have a gene encoding for ampicillin-sensitive PBP5 pbp5S [ 38 ]. Staphylococcus aureus S. With nonfastidious growth requirements, S.

Carriage rates are high in the general population, and transmission can occur by direct contact or airborne routes. Of these isolates, Tackling the problem of MRSA is a top priority for public health systems worldwide, with much current research focused on future intervention strategies. In most cases, glycopeptide antibiotics, for example, vancomycin and teicoplanin, are used as first-line antibiotics for treatment of MRSA infections. However, the selective pressure of these antibiotics has induced some strains to become intermediate-susceptible to vancomycin in vitro, with cases of clinical vancomycin-intermediate and vancomycin-resistant S.

Unfortunately, most VISA isolates are also less susceptible to teicoplanin, with the term glycopeptide-intermediate S. Klebsiella pneumonia K. It is a nonfastidious, Gram-negative bacillus, which is usually encapsulated. Species of the genus Klebsiella are the bacterial pathogens most often found associated with infections in healthcare settings and infections may be endogenous or acquired through direct contact with an infected host.

In recent years, many K. Because carbapenems are conventionally used to treat persistent infections caused by Gram-negative bacteria, the increasing prevalence of carbapenem-resistant K. In addition, the emergence of the K. Even if several intensive infection control practices are used, outbreaks of carbapenemase-mediated multidrug resistant MDR strains are only reduced and cannot be completely eradicated.

An effective treatment is therefore needed to overcome these pathogens. Acinetobacter baumannii Acinetobacter species are widely distributed in the environment and readily contaminate the hospital environment. The most important human pathogen is A. Strains are frequently antibiotic resistant, which is a particular problem in surgical wards and intensive care units [ 49 ].

Recently, the emergence of carbapenemase-producing A. These strains show resistance to both colistin and imipenem, and the combination of resistance genes makes them capable of evading the action of most traditional antibiotic compounds [ 50 , 51 ].

Pseudomonas aeruginosa P. Carriage rates are fairly low in the general population but are higher in hospital inpatients, especially immunocompromised hosts. Many P. The most common mechanism of imipenem resistance in P. The combination of these enzymes leads to high rates of carbapenem resistance amongst P.

The continuous increase of MDR isolates presents a complicated situation for antimicrobial therapy; however, colistin is still effective in most cases [ 51 ]. Enterobacter spp. Enterobacter species are nonfastidious Gram-negative rods that are sometimes encapsulated. They can cause opportunistic infections in immunocompromised, usually hospitalized, patients and contain a wide range of antibiotic resistance mechanisms. These MDR strains are resistant to almost all available antimicrobial drugs, except tigecycline and colistin [ 51 ].

There are a range of antimicrobial resistance mechanisms used by the nosocomial ESKAPE pathogens, including enzymatic inactivation, modification of drug targets, changing cell permeability through porin loss or increase in expression of efflux pumps, and mechanical protection provided by biofilm formation.

Antimicrobial resistance in these pathogens is a major menace to public health systems worldwide and seems likely to increase in the near future as resistance profiles change.

This results in the dearth of potential therapeutic agents in the pipeline that causes real concerns but should trigger research and development of new antibiotics or new approaches to control the infections they cause.

In this context, there are current research efforts which are focused on the introduction of new therapeutic schemes to circumvent these pathogens, including antivirulence strategies, bacteriophage therapy, probiotics, therapeutic antibodies, synthetic inhibitors specific to resistance enzymes or bacterial efflux pumps, and inhibition of biofilm formation.

Competing Interests The authors have declared that no competing interests exist. References 1. Magill S. Multistate point-prevalence survey of health care-associated infections. The New England Journal of Medicine. Klevens R. Estimating health care-associated infections and deaths in U.


ESKAPE Pathogens: Resistance and Virulence Mechanisms and How to Escape Them

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There is No Escape from the ESKAPE Pathogens

Open in a separate window —: no classification in Ambler system. Chromosomally encoded AmpC are usually identified in P. Ambler class D consists of a variety of enzymes, such as oxacillin hydrolyzing enzymes OXA. Furthermore, OXA-type carbapenemases are commonly found in Acinetobacter spp. Specific A.

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