There is No Escape from the ESKAPE Pathogens
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) and are now regarded as critical threats in the fight against antibiotic resistance. The CDC estimates that antibiotic-resistant ESKAPE pathogens are responsible for over 2 million illnesses and approximately 23,000 deaths each year in the United States.
Now let’s try to understand in detail what ESKAPE pathogens are and why they are 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 (UTIs) 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 prior treatment, making them more vulnerable to ESKAPE pathogens. E. faecium has become increasingly resistant to 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 on the 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 people carrying S. aureus in their nose without any illness, and half of those isolates are MRSA [1]. However, it is also the cause of a majority of skin and soft tissue infections that are either hospital- or community-acquired. Oftentimes, 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, and Trimethoprim/Sulfamethoxazole, while intravenous agents include Vancomycin and Daptomycin. The emergence of MRSA is the result of decades of antibiotic misuse. 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 part of the normal flora of the mouth, skin, and intestines. However, K. pneumoniae infections primarily occur in the lungs. These 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 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 multidrug-resistant strains in hospital patients. Regretfully, Carbapenem-Resistant Klebsiella pneumoniae (CRKP) is now resistant to almost all available antibiotics and is associated with high mortality rates.
Acinetobacter baumannii is a Gram-negative water organism that is typically found in respiratory secretions, wounds, and urine of hospitalized patients. It can also be found in irrigating solutions and intravenous fluids in hospital settings [3]. More recently, A. baumannii has become increasingly prevalent in conflict zones such as Iraq, earning the nickname “Iraqibacter.” A higher prevalence of multidrug-resistant strains of A. baumannii was documented in U.S. Army service members after their deployment and return from Iraq [5].
Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen with a mortality rate of 40–60%. It is most frequently observed in hospitalized patients and has developed rapid resistance to antibiotics such as Ciprofloxacin and Levofloxacin [7]. By forming a biofilm on surfaces, P. aeruginosa creates a protective barrier that makes it extremely difficult to eradicate, particularly in cystic fibrosis patients. Biofilm-forming P. aeruginosa in wound infections is a major global health concern, and treating infections caused by MDR P. aeruginosa remains a tremendous challenge and an unmet need in modern medicine.
Enterobacter is a genus that encompasses Gram-negative bacteria that most commonly infect the urinary and respiratory tracts. These species are typically resistant to multiple generations of Penicillins and Cephalosporins. Although these infections can be treated with beta-lactam antibiotics—most reliably carbapenems—new reports show the emergence of β-lactamase-mediated resistance in multidrug-resistant Enterobacter, which presents a growing challenge in treating HAIs.
The underlying cause of this multidrug-resistant crisis 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 excessive use of antibiotics has put selective pressure on bacteria, enabling them to acquire mutations and evolve resistance genes. This has created our modern-day nightmare of so-called superbugs. Addressing this global issue requires a multifaceted approach. We must begin with prevention—by preventing infection, we simultaneously prevent the spread of drug-resistant bacteria and limit the development of new resistance mechanisms. In healthcare settings, improving sanitation is crucial to prevent HAIs in already immunocompromised patients. Advocacy plays a role as well—both in ensuring hospitals uphold the highest sanitation standards and in pushing for international policy reform to regulate antibiotic sales and use. Slowing down the spread of multidrug-resistant strains will also require innovation. The development of novel drugs and next-generation antimicrobial agents is essential.
Here at Emery Pharma, we maintain a large collection of the most difficult-to-treat multidrug-resistant strains of ESKAPE pathogens. We offer a wide range of microbiological services, including minimum inhibitory concentration (MIC) testing, antibiotic resistance and post-antibiotic effect testing, checkerboard synergy studies, time-kill kinetics, etc. to help evaluate the efficacy of new compounds or medical devices against these high-priority pathogens. Our team works closely with innovative biotech companies across the globe to develop the next generation of non-antibiotic antimicrobials and help combat the growing challenge of antibiotic resistance. Contact us today to see how we can help you with your antimicrobial development!
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
- Ach, Liza. “Antibiotic Resistance Within Staphylococcus Aureus.” Microbe Wiki. N.p., 2014. Web
- Chambers, Henry F., “Waves of Resistance: Staphylococcus in the Antibiotic Era.” Nature Reviews. Microbiology. U.S. National Libraries of Medicine, Sept. 2009.
- Cunha, Burke A. “Acinetobacter.”Acinetobacter: Background, Pathophysiology, and Epidemiology. Medscape, 15 March 2016
- 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.
- Howard, Aoife, et al. “Acinetobacter baumannii: an emerging opportunistic pathogen.” Virulence. Landes Bioscience, 01 May 2012.
- 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
- 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
- “MRSA Tracking” Centers for Disease Control and Prevention. 13 April 2016
