Monday Article #14: Multi-drug resistance ESKAPE Pathogens

Multi-drug resistance ESKAPE pathogens- Is there an escape from MDR-ESKAPE pathogens?

Multi-drug resistance pathogens

The very first antibiotic, penicillin, discovered by Sir Alexendar Fleming, played an important role in treating serious infections over decades. However, shortly thereafter, penicillin resistance became a substantial clinical problem and the detection of bacterial resistance continued throughout the golden age of antibiotic discovery. Moreover, many other new antibiotics also failed to keep up with the increasing rates of resistance over the years. In fact, MDR bacteria can evolve and move amongst humans and animals, thereby spreading between countries without any notice. For example, MDR bacteria are also able to spread between countries and there are several studies that have documented the spread of resistant pathogens among Asian countries. One of the recent examples is the spread of New Delhi metallo-beta-lactamase 1 (NDM-1) gene which codes for an enzyme that makes bacteria such as Escherichia coli and Klebsiella pneumoniae resistant to antibiotics. It has disseminated to many Asian countries from India, in a short period of time.

Based on the global antimicrobial surveillance system carried out by World Health Organization (WHO), multi-drug resistance pathogen causes 700,000 deaths each year and are estimated to increase more than 10 million in 2050. It is also estimated that $300 billion to more than $1 trillion per year will be lost globally due to lack of treatment against antibiotic resistance pathogens.

ESKAPE pathogens and Clinical characteristics of ESKAPE pathogens

A survey regarding hospital acquired infections (HAI) in the world have reported high nosocomial infections among patients. A second study conducted in 2002, estimated that approximately 1.7 million patients suffered from HAIs that includes all types of bacterial infections, which contributed to the deaths of 99,000 patients per year. Moreover, the data from hospital surveillance study and reports from Infectious Diseases Society, have referred to a group of nosocomial pathogens as ESKAPE pathogens which are associated with the highest risk of mortality thereby resulting in increased health care costs. World Health Organization (WHO) have also listed ESKAPE pathogens as bacteria that urgently needs new antibiotics. The term “ESKAPE” encompasses six such pathogens with growing multidrug resistance and virulence: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp. According to the urgency of need for new antibiotics, the pathogens have been listed based on the priority levels from most resistant to least resistant.

Enterococcus faecium

Enterococcus faecium is the primary cause of health care-associated infections among immunocompromised patients and are highly resistant towards vancomycin. A surveillance study showed that Vancomycin resistant E. faecium (VREfm) has spread widely throughout the world especially among hospitalized patients and also mainly affects the bloodstream. (De Oliveira et al., 2020). However, the entry passage of VREfm is through bloodstream of hospitalized patients which has been preceded by antibiotic exposure, enabling VREfm predominant. The available treatments for E. faecium significantly rely on second line antibiotic therapy which are tigecycline and daptomycin.

Methicillin-resistant Staphylococcus Aureus (MRSA)

MRSA is a gram-positive bacterium and are also known to be hospital acquired (HA-MRSA) and community acquired (CA-MRSA) pathogen. However, CS-MRSA have typically been associated with skin and soft tissue infections, whereas HA-MRSA strains are associated with severe pneumonia and bloodstream infections. The division between CA- and HA-MRSA strains is becoming indistinct, with CA-MRSA strains now identified to be a causative agent of bloodstream infections in nosocomial setting. Based on the findings, CA-MRSA are much more virulent compared to HA-MRSA and this has led to resistant towards all β-lactams antibiotics. Currently, there are certain development of treatments that can be used to treat such as glycopeptides derivatives.

Klebsiella pneumoniae

K. pneumoniae is a gram-negative bacterium in which it is a hospital acquired infection causing pneumonia and urinary tract infections. The antibiotics that are resistant towards K. pneumoniae are cephalosporins and carbapenems. The genes encoding the enzymes, ESBL and carbapenems have mediate resistant to the available drugs. However, there are available treatments to cure K. pneumonia.

Acinetobacter baumannii

A. baumannii infections typically occurs within hospitalized patients. Between 1987 and 1996, the frequency of both community- and hospital-acquired infections across the United States was observed to rise by 50% between the months of July and October. Since the 1970s, A. baumannii has become increasingly common in temperate climates, a shift largely attributed to improved environmental persistence mechanisms and MDR development. A. baumannii is known to be one of the serious pathogens among ESKAPE organisms as it’s the most resistant towards antibiotics.

Pseudomonas aeruginosa

P. aeruginosa is the Gram-negative nosocomial pathogen, is considered as an epitome of MDR due to its major involvement in causing chronic and nosocomial diseases. This high rate of resistance is directly related to their various inherent resistance mechanisms expressed, including the down-regulation of porin manufacturing system (carbapenems and cefepime), overexpression of efflux pumps (carbapenems) or production of other beta-lactamases besides the high production of AmpC beta-lactamase.

Enterobacter aerogenes

MDR Enterobacter species are an increasing cause of hospital-acquired infection. Enterobacter pathogens are gram negative in which triggers urinary tract infection and blood diseases (Mulani et al., 2019). They can also cause opportunistic infections in immunocompromised, usually hospitalized, patients and contain a wide range of antibiotic resistance mechanisms. Many Enterobacter strains contain ESBLs and carbapenemases, including VIM, OXA, metallo-β-lactamase-1, and KPC. Currently, the available antibiotic treatments for Enterobacter species are only tigecycline and colistin.

Studies from WHO report has also shown very high rates of resistance in ESKAPE pathogens. Prolonged drug exposure and nonstop viral replication result in the advent of various resistant strains and persistence of infections despite therapy. This has made antiviral resistance a matter of concern in immunocompromised patients. Their clinical importance relies on their virulence and ability in developing mechanisms to decrease susceptibility to antimicrobials, increasing inappropriate therapy and affecting negatively on ICU patients’ outcome. Table 1 shows the clinical characteristics of ESKAPE pathogens.

Resistance mechanism of ESKAPE pathogens

Mechanism of drug resistant fall into several categories which includes inactivation or alteration of drug, modifications of drug binding sites, and changes in cell permeability resulting in reduced intracellular drug accumulation.

Drug Inactivation or Alteration

Bacteria produces enzymes that has the ability to modify and inactivate the antibiotics. Such are β-lactamases, aminoglycoside-modifying enzymes, or chloramphenicol acetyltransferases. Among these enzymes, β-lactamases are known to be highly prevalent and act by hydrolyzing the β-lactam ring which is present in all β-lactams; thus, all penicillins, cephalosporins, monobactams, and carbapenems are essential to their activity. β-lactamases are classified as the most clinically important β-lactamases as those produced by Gram-negative bacteria. Besides that, Ambler class A enzymes that consist of penicillinase, cephalosporinase, broad-spectrum β-lactamases, extended-spectrum β-lactamases (ESBLs), and carbapenemases. They can inactivate penicillins, third-generation oxyimino-cephalosporins, aztreonam, cefamandole, cefoperazone, and methoxy-cephalosporins. The Ambler class A group contains a number of significant enzymes including ESBLs. Carbapenemases are also prevalent in clinical bacterial isolates such as K. pneumonia such as KPC-1 that results in resistance to imipenem, meropenem, amoxicillin/clavulanate, piperacillin/tazobactam, ceftazidime, aztreonam, and ceftriaxone.

Modification of drug binding sites

Certain resistant bacteria have the ability to avoid recognition by antimicrobial agents by modifying their target sites. The mutation of gene encoding for penicillin-binding proteins (PBPs), which are known as the enzymes that typically anchored on the cytoplasmic membrane of the bacterial cell wall. Its function is to assembly and control the latter stages of the cell wall building, which results in the expression of unique penicillin-binding proteins. For example, bacterial cell wall synthesis in methicillin-resistant Gram-positive organisms can be inhibited by glycopeptides, which target residues of peptidoglycan precursors. However, by changing the peptidoglycan cross-link target, encoded by a complex gene cluster, E. faecium and E. faecalis can increase their resistance to glycopeptides in current clinical use (vancomycin and teicoplanin).

Reduced Intracellular Drug Accumulation

Reducing the amount of antibiotic able to pass through the bacterial cell membrane is one of the strategies used by bacteria to develop antibiotic resistance. In order to achieve these mechanisms, the bacteria includes the occurrence of diminished protein channels on the bacterial outer membrane to decrease drug entry and the presence of efflux pumps which on the other hand decrease the amount of drug accumulated within the cells.

Porin Loss

The proteins that are on the outer membrane of Gram-negative bacteria are known as porins. The function of porins is that it forms channels that allow the passage of hydrophilic substances which includes antibiotics. For example, a decrease of porin protein OprD of P. aeruginosa reduces drug influx into the cell, allowing the bacterium to develop resistance towards the antimicrobial drug. Multiple-drug resistant K. pneumoniae strains also exhibit resistant/reduced susceptibility to β-lactams (such as cephalosporins and carbapenems) by the loss of outer membrane proteins known as OmpK35 and OmpK36 together with the production of resistance enzymes, including AmpC β-lactamase.

Efflux Pumps

In order 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.

An emerging increase in MDR among ESKAPE pathogens have raised concerns if there will be an alternative antimicrobial drug to combat these pathogens in future. However, many research are being carried out on developing different types of antimicrobial therapy. The most prominent ones are antibiotics in combination, bacteriophage therapy, antimicrobial peptides, and silver nanoparticles. Besides this antimicrobial therapy, many research are also being done on plants. Based on varieties of studies, natural products, widely derived from culinary plants, have been exploited as a resource in drug development. This is because, culinary plants were utilized as traditional medicines in poor or developing countries since ancient times as it has been the key source for drugs and an alternative medicine to fight against infectious diseases.

References

• Bhatia, R. (2019). Antimicrobial Resistance in developing Asian countries: burgeoning challenge to global health security demanding innovative approaches. Global Biosecurity, 1(2).

• Bickenbach, J., Schöneis, D., Marx, G., Marx, N., Lemmen, S., & Dreher, M. (2018). Impact of multidrug-resistant bacteria on outcome in patients with prolonged weaning. BMC pulmonary medicine, 18(1), 1-8.

• Calixto, J. B., Santos, A. R., Filho, V. C., & Yunes, R. A. (1998). A review of the plants of the genus Phyllanthus: their chemistry, pharmacology, and therapeutic potential. Medicinal research reviews, 18(4), 225-258.

• Castanheira, M., Deshpande, L. M., Mathai, D., Bell, J. M., Jones, R. N., & Mendes, R. E. (2011). Early dissemination of NDM-1-and OXA-181-producing Enterobacteriaceae in Indian hospitals: report from the SENTRY Antimicrobial Surveillance Program, 2006-2007. Antimicrobial agents and chemotherapy, 55(3), 1274-1278.

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This article was prepared by Tanessri Muni Peragas