What are the mechanisms by which Enterococcus species confer antibiotic resistance?

Mechanisms of Enterococcal Antibiotic Resistance

Enterococci confer antibiotic resistance through both intrinsic mechanisms inherent to the species and acquired mechanisms obtained via horizontal gene transfer of mobile genetic elements including plasmids, conjugative transposons, and other mobile DNA that carry resistance determinants. 1, 2

Intrinsic Resistance Mechanisms

Enterococci possess natural, species-level resistance to multiple antibiotic classes that limits therapeutic options from the outset:

• Cell wall structure and permeability barriers provide intrinsic resistance to virtually all cephalosporins, clindamycin, and trimethoprim-sulfamethoxazole in both E. faecalis and E. faecium 2
• Low-level aminoglycoside resistance occurs intrinsically due to poor drug uptake across the bacterial cell envelope, though this does not prevent synergistic killing when combined with cell wall-active agents 3
• Penicillin-binding protein alterations in E. faecium result in higher baseline penicillin MICs (typically ≥16 μg/mL) compared to E. faecalis (typically 2-4 μg/mL) 3

Acquired Resistance Mechanisms

Aminoglycoside Resistance

• Plasmid-mediated aminoglycoside-modifying enzymes represent the most common mechanism, with the AAC(6')-APH(2") bi-functional enzyme conferring high-level resistance to gentamicin and all related aminoglycosides except streptomycin 3, 4
• Phosphotransferases in enterococci provide enzymatic inactivation of aminoglycosides 5
• These resistance genes are carried on both narrow and broad host-range plasmids and conjugative transposons, facilitating rapid dissemination between enterococcal strains and potentially to other Gram-positive pathogens 4

Beta-Lactam Resistance

• Inducible β-lactamase production occurs in some E. faecalis strains, detectable only with 100-fold higher inocula than standard testing, but this enzyme is inhibited by sulbactam and clavulanic acid 3
• Altered penicillin-binding proteins through mutation of intrinsic genes lead to high-level ampicillin resistance, particularly in E. faecium 2

Glycopeptide Resistance

• VanA genotype confers high-level vancomycin resistance (MIC ≥64 μg/mL) through production of modified peptidoglycan precursors ending in D-Ala-D-Lac instead of D-Ala-D-Ala, eliminating vancomycin's binding target 3, 6
• VanB genotype produces intermediate to high-level resistance (MIC 16-512 μg/mL) through similar peptidoglycan modification mechanisms 3, 6
• VanC genotype is intrinsically present in E. casseliflavus and E. gallinarum, causing low to intermediate-level resistance (MIC 2-32 μg/mL) 3
• Horizontal gene transfer of vanA and vanB occurs primarily in E. faecium and some E. faecalis strains via plasmids and conjugative transposons, with documented transmission to other Gram-positive pathogens including methicillin-resistant S. aureus 3, 6

Mobile Genetic Elements as Resistance Traffickers

• Conjugative plasmids, particularly pheromone-responsive plasmids and broad host-range incompatibility group 18 plasmids, serve as the primary vehicles for resistance gene dissemination 7
• Conjugative transposons carry resistance genes and can integrate into chromosomal DNA, providing stable inheritance and facilitating transfer between distantly related bacterial species 4, 7
• Multidrug resistance commonly occurs because mobile genetic elements carry genes encoding resistance to multiple unrelated antimicrobial classes simultaneously 5, 8
• Genome plasticity is promoted by these mobile elements through recombination and rearrangement, generating novel resistance phenotypes 7

Clinical Implications and Resistance Transmission

• Environmental reservoirs are established when resistant enterococci colonize the gastrointestinal tract of humans and animals, persisting even after antibiotic pressure ceases because resistance genes are inherited by bacterial progeny 5, 8
• Cross-species transmission occurs readily in healthcare settings, with enterococci serving as a reservoir and trafficking hub for resistance determinants that can reach more virulent pathogens 8, 7
• Multidrug-resistant phenotypes are increasingly common, with vancomycin-resistant E. faecium often exhibiting concurrent high-level resistance to penicillins and aminoglycosides, severely limiting therapeutic options 3, 6

Critical Pitfalls

• The remarkably plastic genome of enterococci allows rapid acquisition of new resistance mechanisms through both mutation and horizontal gene transfer, making resistance patterns unpredictable 2
• Automated laboratory methods may fail to detect certain resistance phenotypes, particularly VanB with moderate resistance levels, leading to inappropriate therapy 6
• Standard inoculum testing misses inducible β-lactamase production in E. faecalis, requiring 100-fold higher bacterial concentrations for detection 3