The ESKAPE pathogen mnemonic was created to represent deadly bacterial pathogens with rapidly growing multi-drug resistant properties. ESKAPE stands for Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species. These pathogens are notoriously responsible for some of the deadliest hospital-acquired infections (HAIs). The CDC estimates antibiotic resistant ESKAPE pathogens cause over 2 million illnesses and approximately 23,000 deaths per year.

Now let’s try to understand in detail what ESKAPE pathogens are and why are they important in healthcare and modern-day antimicrobial development.

 

Enterococcus faecium is a Gram-positive bacterium that is commonly found in the gastrointestinal tract of humans, and is well known for its role in causing urinary tract infections, endocarditis, wound infections, and nosocomial bacteremia that can lead to sepsis. Enterococcus faecium is highly virulent. One epidemiological report showed that in October 1990, a strain of E. faecium highly resistant to glycopeptides, penicillins, and aminoglycosides was isolated from a patient in an intensive care unit. Following this, multi-drug resistant strains of E. faecium were isolated from cultures of blood, urine, or surgical wound specimens from eight additional patients indicating the rapid spread of these drug resistant infectious agents [4]. Among the variety of diseases caused by E. faecium, urinary tract infections (UTI) are the most prevalent with approximately 110,000 cases each year[6]. Many of these cases are nosocomial, and often the patients are immunocompromised due to a prior treatment, making them more vulnerable to ESKAPE pathogens. E. faecium have become increasingly resistant against antibiotics such as Penicillin, Gentamicin, Tetracycline, Erythromycin, and even Vancomycin, a last resort treatment against Gram-positive bacteria.

 

Staphylococcus aureus is a Gram-positive bacterium commonly found in the nose and skin of healthy people. S. aureus possesses a method of gene transfer that allows it to acquire resistance to most antibiotics, particularly Methicillin, creating a unique superbug called Methicillin resistant S. aureus (MRSA) S. aureus is known for its asymptomatic colonization of humans with 1 in 3 humans carrying S. aureus in their nose without any illness, and half of those isolated are MRSA [1]. However, it is the cause of a majority of skin and soft tissue infections that are either hospital or community acquired. Often times, MRSA can lead to severe, purulent skin and soft tissue infections. Additionally S. aureus blood infections can potentially lead to sepsis. Few antibiotics offer coverage for MRSA. Orally administered agents include Clindamycin, Doxycycline, trimethoprim/sulfamethoxazole, Linezolid. Intravenous agents include Vancomycin, Daptomycin, etc. The emergence of MRSA is the result of misuse of antibiotics treatment over the course of decades. According to the CDC, there are about 80,000 cases and 11,000 deaths due to infection by invasive MRSA strains each year.

Klebsiella pneumoniae is a Gram-negative non-motile bacterium commonly found in low numbers as normal flora of the mouth, skin and intestines. However, K.  pneumoniae infections primarily occur in the lungs. K.  pneumoniae infections are major HAIs and patients on ventilators and catheters or with surgical wounds are at higher risk of acquiring this infection, which causes necrosis, inflammation, and hemorrhage within the lung tissue and can also result in UTIs. This pathogen is one of the most prevalent in ICUs and has developed increasing resistance to carbapenems since the 1990s [2]. Carbapenems are last resort antibiotics typically used to treat multi-drug resistant strains in hospital patients. Regretfully, now Carbapenem Resistant Klebsiella pneumoniae (CRKP) is resistant to almost all available antibiotics and is associated with high rates of mortality.

 

Acinetobacter baumannii is a Gram-negative water organism that can typically be found in respiratory secretions, wounds, and urine of hospitalized patients. It can also be found in irrigating solutions and intravenous solutions in the hospital setting [3]. Most recently, A. baumannii has become increasingly prevalent in conflict zones such as Iraq, earning the name “Iraqibacter.” Higher prevalence of multidrug resistant strains of A. baumannii was documented in US Army Service members after their duty and return from Iraq [5].

 

Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen with a mortality rate of 40-60%. P. aeruginosa is most frequently observed in hospitalized patients and the bacteria has developed rapid resistance to antibiotics such as Ciprofloxacin and Levofloxacin [7].By forming a biofilm on surfaces, P. aeruginosa creates a “shield” making it extremely difficult to destroy, specifically in cystic fibrosis patients. Biofilm forming P. aeruginosa in wound infections is a major health concern globally and treating infections caused by MDR P. aeruginosa is unarguably a tremendous challenge that remains an unmet need in modern medicine.

 

Enterobacter is a genus that encompasses Gram-negative that most commonly infects the urinary and respiratory tracts. These species are typically resistant to multiple generations of Penicillins and Cephalosporins. Though these infections can be treated with beta-lactam antibiotics, most reliably carbapenems, new reports show the emergence of alarming rate of β-lactamase-mediated resistance in multidrug-resistant Enterobacter which is a major concern in treating HAIs.

The underlying cause of this multi-drug resistant issue is the overuse and misuse of antibiotics around the globe. In many developing countries, patients have the ability to purchase antibiotics over the counter, leading to a tremendous amount of antibiotic misuse. Inappropriate and increased use of antibiotics has put selective pressure to acquire mutations allowing these bugs to evolve resistant genes, creating our modern-day nightmare of superbugs. We must take a multi-faceted approach to stop these superbugs from spreading, and this starts with prevention. By preventing infection, we are also preventing the spread of drug resistant bacteria and limiting the development of new drug resistance. Additionally, we must improve hospital sanitation to avoid HAIs in patients that may already be immunocompromised. This means being a patient advocate in making sure the highest sanitation measures are being taken. We must also advocate to change public policy in foreign countries to stop people from self-medicating with antibiotics. This will likely slow down the spread of multi-drug resistant strains around the globe. The last way to combat this problem is through the development of novel drugs and antimicrobial agents.

Here at Emery Pharma, we maintain a large collection of the most difficult to treat multi-drug resistant strains of ESKAPE pathogens.  We provide an array of microbiological services that can help test your compound or medical device against any of these ESKAPE pathogens. We are working with a number of groundbreaking biotech companies around the world in developing the next generation of non-antibiotic antimicrobials.

 

About the Authors:

Ana Najafi holds a Pharm.D. from UCSF.

Sri Arumugam holds a Ph.D. degree in Microbiology.

Illustration Credit: Aisling Sinclair

References

1. Ach, Liza. “Antibiotic Resistance Within Staphylococcus Aureus.” Microbe Wiki. N.p., 2014. Web
2. Chambers, Henry F., “Waves of Resistance: Staphylococcus in the Antibiotic Era.” Nature Reviews. Microbiology. U.S. National Libraries of Medicine, Sept. 2009.
3. Cunha, Burke A. “Acinetobacter.”Acinetobacter: Background, Pathophysiology, and Epidemiology. Medscape, 15 March 2016
4. Handwerger, Sandra, et al. “Nosocomial outbreak due to Enterococcus faecium highly resistant to vancomycin, penicillin, and gentamicin.” Clinical Infectious Diseases 16.6 (1993): 750-755.
5. Howard, Aoife, et al. “Acinetobacter baumannii: an emerging opportunistic pathogen.” Virulence. Landes Bioscience, 01 May 2012.
6.  Kau, Andrew, et al. “Enterococcus faecalis Tropism for the Kidneys in the Urinary Tract of C57BL/6J Mice.” American Society for Microbiology. 01 April 2005
7. Lister, Phillip D, et al. “Antibacterial-Resistant Pseudomonas aeruginosa: Clinical Impact and Complex Regulation of Chromosomally Encoded Resistance Mechanisms.” Clinical Microbiology Reviews. American Society for Microbiology. Oct. 2009
8. “MRSA Tracking” Centers for Disease Control and Prevention. 13 April 2016