What are Enterobacterales?

What are Enterobacterales?

Enterobacterales is an order of Gram-negative bacteria that includes common intestinal and nosocomial pathogens such as Escherichia coli, Klebsiella pneumoniae, Enterobacter species, Serratia marcescens, Citrobacter species, and Proteus species 1.

Taxonomic Classification

Enterobacterales represents a comprehensive taxonomic revision of what was previously known as the "Enterobacteriaceae family." Based on genome-scale phylogenetic analysis using 1,548 core proteins, this order is now divided into seven distinct families 1:

• Enterobacteriaceae (includes E. coli, Klebsiella, Enterobacter)
• Erwiniaceae
• Pectobacteriaceae
• Yersiniaceae (includes Yersinia species)
• Hafniaceae (includes Hafnia)
• Morganellaceae (includes Proteus, Morganella)
• Budviciaceae

This taxonomic structure reflects phylogenetic relationships that were not consistently resolved using traditional 16S rRNA gene sequencing alone 1.

Clinical Significance

Primary Colonization Sites

Enterobacterales are facultative anaerobic bacteria that normally colonize the gastrointestinal and urinary tracts 2. In hospitalized patients, intestinal colonization density is remarkably high, with mean colonization rates of 27.5-31.1% 2. These organisms behave as allochthonous (non-native) flora when found in the oral cavity or oropharynx 3.

Pathogenic Potential

These organisms cause both community-acquired and healthcare-associated infections, including:

• Bloodstream infections (BSI)
• Urinary tract infections (UTI)
• Intra-abdominal infections (IAI)
• Pneumonia (hospital-acquired and ventilator-associated)
• Complicated skin and soft tissue infections 4, 5

In blood culture surveillance, K. pneumoniae (52.2%) and E. coli (34.9%) represent the most frequently isolated Enterobacterales from bloodstream infections 6.

Antimicrobial Resistance Patterns

Resistance Mechanisms

Enterobacterales harbor multiple resistance mechanisms that pose serious therapeutic challenges 7:

Extended-Spectrum β-Lactamases (ESBLs):

• ESBL production rates reach 81% in Klebsiella spp. and 47% in E. coli 6
• CTX-M-type ESBLs have gained particular importance globally 4
• ESBL-producing strains exhibit co-resistance to fluoroquinolones, aminoglycosides, and trimethoprim-sulfamethoxazole 4

Carbapenemase Production: The most clinically significant resistance mechanism involves carbapenemase enzymes, classified by the Ambler system 7:

• Class A: KPC (Klebsiella pneumoniae carbapenemase) - most common globally at 47.4%
• Class B: Metallo-β-lactamases (MBLs) including NDM, VIM, IMP - account for 20.6%
• Class D: OXA-48-like enzymes - represent 19.0%

MBLs are particularly concerning because they hydrolyze all β-lactam classes except aztreonam and cannot be inhibited by classic serine β-lactamase inhibitors 7.

AmpC β-Lactamases:

• Can be chromosomally encoded (cAmpC) in species like Enterobacter spp., Citrobacter freundii, and Serratia marcescens
• Plasmid-encoded (pAmpC) variants can transfer to species normally lacking these enzymes 8
• Inducible production leads to treatment failures with third-generation cephalosporins despite initial susceptibility 8

Geographic and Temporal Trends

Carbapenem resistance has increased more than seven-fold since 2006 in Europe, with some countries (Italy, Greece) reporting resistance rates exceeding 50% in K. pneumoniae 7. Recent data from 2023 show carbapenem resistance rates reaching 36.3% among Enterobacterales bloodstream isolates, with particularly high rates (58.1%) in Klebsiella spp. 6.

The highest ESBL carriage rates occur in the Western Pacific, Eastern Mediterranean, and Southeast Asia regions, driven by poor water access, pollution, and high population density 5.

Clinical Impact and Outcomes

Infections caused by resistant Enterobacterales significantly increase morbidity, mortality, and healthcare costs 4:

• ESBL-producing infections result in median hospital charges of $66,590 versus $22,231 for non-ESBL infections 4
• Treatment failure rates at 72 hours reach 35% for ESBL-producing K. pneumoniae bacteremia versus 15% for susceptible strains 4
• Approximately one in three patients with carbapenem-resistant K. pneumoniae infections die, with less than 70% achieving clinical or microbiological response to traditional antibiotics 7

Infection Risk Factors

Intestinal dominance by Enterobacterales correlates with subsequent infection risk, with both absolute and relative abundance playing roles 2. Risk factors for ESBL-producing infections include 5:

• Recent antibiotic exposure (particularly third-generation cephalosporins or fluoroquinolones) within 90 days
• Known colonization with ESBL-producing organisms
• Recent hospitalization within 90 days
• Residence in long-term care facilities
• Home intravenous therapy or hemodialysis within 30 days

Treatment Implications

Carbapenem-Resistant Enterobacterales (CRE)

Rapid identification of specific carbapenemase families (KPC, NDM, VIM, OXA-48-like) is strongly recommended to guide targeted therapy 7. Time from blood culture collection to active antibiotic therapy directly influences outcomes in critically ill patients 7.

For KPC-producing CRE, novel β-lactam agents (ceftazidime-avibactam and meropenem-vaborbactam) should be first-line treatment options (strong recommendation, moderate certainty) 7. Imipenem-relebactam and cefiderocol may also be considered (conditional recommendation, low certainty) 7.

Third-Generation Cephalosporin-Resistant Enterobacterales (3GCephRE)

For community-acquired infections without ESBL risk factors, narrower-spectrum agents are preferred 5, 9. However, when ESBL production is confirmed or suspected, carbapenems remain the preferred option for severe infections, though cefepime is supported as a carbapenem-sparing alternative in select cases 8.

Colistin emerged as the most effective antibiotic overall, with E. coli showing only 0.6% resistance and low meropenem resistance (1.5%) 6.

Common Pitfalls

1. Assuming susceptibility based on initial testing: Inducible AmpC producers may appear susceptible to third-generation cephalosporins but develop resistance during therapy 8

2. Overlooking Enterobacter species: While surveillance focuses on K. pneumoniae and E. coli, Enterobacter spp. represent an underrecognized carbapenemase reservoir in Europe 10

3. Ignoring colonization status: High intestinal colonization density precedes infection and represents an intervention opportunity 2

4. Geographic assumptions: ESBL and carbapenemase prevalence varies dramatically by region, requiring local epidemiological knowledge 5