ESKAPE Pathogens: The Six, Gram Status, and Why They Resist Antibiotics

A patient in intensive care, already on a ventilator and a urinary catheter, develops a new fever. The blood culture grows a bacterium that shrugs off the first antibiotic, then the second, then the carbapenem that was supposed to be the last line. This scenario plays out in hospitals worldwide, and most of the time the culprit is one of just six organisms.

They are grouped under a single, deliberately chosen acronym: ESKAPE, because they escape the drugs we have. This article covers the six, sorts out which is which (including the two confusable Entero- organisms), and explains the resistance tricks they share.

ESKAPE is an acronym for six nosocomial (hospital-acquired) bacteria that can “escape” the action of commonly used antibiotics through multidrug resistance (MDR). The six are Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species. The acronym was popularized by the Infectious Diseases Society of America (Rice, 2008) to focus attention on the pathogens most in need of new drugs.

ESKAPE is often confused with the WHO Bacterial Priority Pathogens List, and the two overlap heavily, but they are not the same thing. ESKAPE is an older, memory-friendly acronym for six specific organisms; the WHO list is an official, tiered priority ranking (updated in 2024) covering a broader set of pathogens. Most ESKAPE organisms appear near the top of the WHO list, which is why the two are so often mentioned together.

See our article on the WHO Bacterial Priority Pathogens List for the current tiered ranking.

Across the group, ESKAPE organisms have acquired resistance to multiple antibiotic classes, including β-lactams, fluoroquinolones, aminoglycosides, macrolides, and in the hardest cases the carbapenems that serve as last-line agents. The sections below show how each organism does this.

Figure: ESKAPE Pathogens

Enterococcus vs Enterobacter: telling the two "E" organisms apart

The single most confusing thing about ESKAPE is that two of its members have similar names and both start with E, yet they are completely different bacteria. Getting them straight is worth a moment.

The quickest way to keep them apart: Enterococcus is a Gram-positive coccus whose headline problem is vancomycin resistance (VRE). Enterobacter is a Gram-negative rod whose headline problem is carbapenem/β-lactam resistance. Same first three letters, opposite Gram reaction, opposite drug story.

A further note on the S and the E: do not confuse Enterobacter (the Gram-negative rod) with the whole order Enterobacterales (which also contains Klebsiella and E. coli), or with Enterococcus (the Gram-positive coccus).

Which ESKAPE pathogens are Gram-positive and which are Gram-negative?

Only two of the six are Gram-positive; the other four are Gram-negative. This split matters because it predicts the wall structure, the resistance mechanisms, and even which drugs are options.

Memory hook: the two cocci are the two Gram-positives (Enterococcus and Staphylococcus). Everything else in ESKAPE is a Gram-negative rod-shaped (or coccobacillary) organism. If you can picture the shape, you know the Gram reaction.

The six ESKAPE pathogens at a glance

E = Enterococcus faecium (Gram-positive coccus). A normal gut commensal that turns opportunistic in hospitalized patients, causing UTIs, endocarditis, and bacteremia. Its signature threat is vancomycin-resistant Enterococcus (VRE), and it can transfer that vancomycin-resistance gene to other bacteria. Note: ESKAPE's E is E. faecium; the closely related E. faecalis is a separate species. For the genus in depth, see our article on Enterococcus.

S = Staphylococcus aureus (Gram-positive coccus). A nasal and skin colonizer that causes wound infections, pneumonia, osteomyelitis, bacteremia, and toxic shock. Its signature threat is methicillin resistance (MRSA), driven by an altered penicillin-binding protein (PBP2a). For depth, see our articles on Staphylococcus aureus and on MRSA.

K = Klebsiella pneumoniae (Gram-negative rod). A capsulated enteric rod causing hospital pneumonia and catheter-associated UTIs. Its signature threat is β-lactamase-driven resistance: ESBLs and, increasingly, carbapenemases (KPC), making some strains resistant to nearly all β-lactams. For depth, see our article on Klebsiella pneumoniae.

A = Acinetobacter baumannii (Gram-negative coccobacillus). An environmental opportunist that thrives in the ICU, causing ventilator pneumonia, bacteremia, and wound infection. Its signature threat is carbapenem resistance (CRAB), via carbapenemases and efflux pumps. For depth, see our article on Acinetobacter.

P = Pseudomonas aeruginosa (Gram-negative rod). An environmental organism and opportunist in immunocompromised and burn patients. Its signature threats are carbapenem resistance (via porin loss, e.g. to imipenem) and efflux-pump-driven resistance to fluoroquinolones and aminoglycosides. For depth, see our article on Pseudomonas aeruginosa.

E = Enterobacter species (Gram-negative rod). Enterobacterales opportunists (mainly E. cloacae; note that the former E. aerogenes is now Klebsiella aerogenes) causing infections in immunocompromised inpatients. Their signature threat is β-lactam resistance through ESBLs, KPC, and AmpC β-lactamases; MDR strains may be susceptible only to agents such as tigecycline and colistin. For depth, see our article on Klebsiella pneumoniae.

Resistance mechanism by organism

The pattern to notice: the two Gram-positives resist by altering the drug's target (PBP2a in MRSA, peptidoglycan terminus in VRE), while the Gram-negatives mostly resist by destroying or excluding the drug (β-lactamase enzymes, porin loss, efflux pumps). Target change vs. drug exclusion is the underlying logic of the whole group.

How Do these Bacteria Develop Resistance?

The Capability of Modifying Sites of Drug Binding

Some bacteria resist a drug by changing the target the drug is supposed to bind, so the antibiotic can no longer attach. The clearest example is MRSA: it makes an altered penicillin-binding protein, PBP2a, that β-lactams bind poorly, so the drug fails to block cell-wall synthesis. See the resistance table above for which ESKAPE organism uses this and the other mechanisms.

The Ability to Transfer the Resistant Gene

Studies have shown that Enterococci species can transfer their vancomycin-resistance 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. Porins are proteins in the outer membrane that form channels through which hydrophilic drugs (like many antibiotics) enter the cell. By losing or reducing these porins, the bacterium shuts the door: fewer drug molecules get in, and resistance rises, particularly to carbapenems such as imipenem and meropenem.

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.
• The most important of these in Gram-negative ESKAPE organisms is the resistance-nodulation-division (RND) family, a poly-selective pump that can expel several different drug classes at once, which is why a single pump can produce resistance to many antibiotics simultaneously.

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 make biofilms in healthcare settings.

How to Remember

The acronym spells its own meaning: these six ESCAPE antibiotics. ESKAPE = Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter. The name is the mnemonic; the work is remembering which is which.

Two cocci, two Gram-positives. The only Gram-positive members are the two cocci (Enterococcus, Staphylococcus). The other four are Gram-negative rods/coccobacilli.

Pair each organism with its signature drug it resists. VRE = vancomycin (Enterococcus). MRSA = methicillin (Staph). The Gram-negatives = the β-lactams and carbapenems (Klebsiella, Acinetobacter, Pseudomonas, Enterobacter). Learn the organism-drug pair, not a list.

Gram-positives change the target; Gram-negatives exclude or destroy the drug. The two mechanisms split cleanly along the Gram line, which is the deepest way to remember how each resists.

Enterococcus vs Enterobacter: coccus vs rod, vancomycin vs carbapenem. The two confusable E's differ in Gram reaction, shape, and signature drug. Same first letters, opposite everything else.

Key exam facts

Where Students Get Confused

"What is the difference between Enterococcus and Enterobacter?" They are entirely different bacteria that happen to share the first letters. Enterococcus faecium is a Gram-positive coccus whose signature resistance is to vancomycin (VRE). Enterobacter is a Gram-negative rod whose signature resistance is to β-lactams and carbapenems. Coccus versus rod, Gram-positive versus Gram-negative, vancomycin versus carbapenem: opposite in almost every way except the name.

"Is ESKAPE the same as the WHO priority pathogens list?" No, though they overlap. ESKAPE is an older acronym coined by the IDSA for six specific hospital pathogens. The WHO Bacterial Priority Pathogens List is an official, tiered ranking (updated 2024) covering a broader set. Most ESKAPE organisms sit near the top of the WHO list, which is why they are mentioned together, but the two are not identical.

"Are ESKAPE pathogens Gram-positive or Gram-negative?" Both. Two are Gram-positive (the cocci: Enterococcus and Staphylococcus) and four are Gram-negative (the rods: Klebsiella, Acinetobacter, Pseudomonas, Enterobacter). The split predicts their resistance style.

"Is ESKAPE's E for faecium or faecalis?" For Enterococcus faecium. Both E. faecium and E. faecalis cause human infection, but faecium carries the greater vancomycin-resistance (VRE) burden and is the species named in ESKAPE. They are different species and should not be treated as interchangeable.

"Why are these six grouped together?" Because they share a clinical problem, not a taxonomy. All six are common causes of hospital-acquired infection, all six readily develop multidrug resistance, and together they account for a large share of infections that "escape" available antibiotics. The group is defined by behavior (resistance in the hospital), which is why it mixes Gram-positive cocci and Gram-negative rods.

References

1. Rice LB. Federal funding for the study of antimicrobial resistance in nosocomial pathogens: no ESKAPE. J Infect Dis. 2008;197(8):1079-1081.
2. Santajit S, Indrawattana N. Mechanisms of antimicrobial resistance in ESKAPE pathogens. Biomed Res Int. 2016;2016:2475067. https://doi.org/10.1155/2016/2475067
3. Navidinia M. The clinical importance of emerging ESKAPE pathogens in nosocomial infections. J Paramed Sci. 2016;7(3):43-57.
4. World Health Organization. WHO Bacterial Priority Pathogens List, 2024. Geneva: WHO; 2024. Available from: https://www.who.int/publications/i/item/9789240093461
5. Murray PR, Rosenthal KS, Pfaller MA. Medical Microbiology. 9th ed. Elsevier; 2020.