🧬 Why Enterococcus Is Resistant to Cephalosporins (and How Amoxicillin Changes the Game)

FRCPath Prep Medical Microbiology Consultants
Jul 26
2 min read

📅 Published: July 26, 2025

📚 Category: Antimicrobial Resistance | Mechanisms | FRCPath Part 1 & 2

🔬 Author: Team FRCPathPrep

🦠 The Puzzle: Why Don’t Cephalosporins Work Against Enterococcus?

Enterococci (E. faecalis and E. faecium) are intrinsically resistant to cephalosporins — and the reason lies in their penicillin-binding proteins (PBPs).

🔍 The Science Behind It: PBP Profiles in Enterococcus

Enterococcus species have a unique PBP architecture:

Species	Key Low-Molecular-Weight PBPs
E. faecalis	PBP4 and PBP5
E. faecium	PBP5 (dominant), lesser PBP4

These PBPs are essential for cell wall synthesis.
Cephalosporins bind poorly to these low-affinity PBPs.
Instead, cephalosporins target PBP2 and PBP3, which are not essential for Enterococcal survival.

🧠 Result? The bacteria continue forming their cell wall and survive despite high-dose cephalosporin use.

💊 Enter Amoxicillin: A Partial Solution

Amoxicillin, a beta-lactam, partially inhibits PBP4 and PBP5, offering a degree of suppression over critical cell wall machinery.

This partial inhibition is:
- 💥 Sufficient to lyse E. faecalis
- ⚠️ Not enough to kill E. faecium unless PBP5 is completely inhibited

🔗 Why Amoxicillin + Cephalosporin Combo Works (in Some Cases)

Interestingly, using amoxicillin with a cephalosporin (e.g. ceftriaxone) broadens PBP coverage:

Amoxicillin hits PBP4 & PBP5 (partial)
Cephalosporin targets PBP2 & PBP3

🧬 This combined inhibition may produce a synergistic effect, especially against E. faecalis (Maynardi 1995, Beganovic 2018).

🧪 This strategy is sometimes used as an aminoglycoside-sparing regimen in E. faecalis endocarditis when gentamicin is contraindicated.

📌 Clinical Implication Table

Antibiotic	Binds to	Effectiveness vs Enterococcus
Cephalosporins	PBP2, PBP3	❌ Ineffective (low-affinity PBPs untouched)
Amoxicillin	PBP4, PBP5 (partial)	✅ Active (esp. E. faecalis)
Amox + Gentamicin	PBP4/5 + ribosome	✅✅ Bactericidal (if no HLAR)
Amox + Ceftriaxone	Broader PBP inhibition	✅ Alternative synergy in E. faecalis

🔬 Summary for FRCPath

🛑 Intrinsic cephalosporin resistance in Enterococcus is due to low-affinity PBPs (4 & 5).
✅ Amoxicillin partially inhibits these PBPs → clinically useful against E. faecalis.
🔗 Combining amoxicillin with ceftriaxone or aminoglycosides broadens target coverage and enhances killing.
❗ Complete PBP5 inhibition needed for E. faecium lysis.

📚 Key References

Maynardi AJ et al. Mechanisms of cell lysis in enterococci. (1995)
Beganovic M et al. Enterococcal resistance patterns and synergy mechanisms. (2018)