Mechanism of Action of Glycopeptides (e.g., Vancomycin)

Introduction

Glycopeptides, most notably vancomycin, are a class of bactericidal antibiotics that inhibit bacterial cell wall synthesis by a mechanism distinct from β-lactams. Vancomycin is a crucial agent against Gram-positive infections, especially methicillin-resistant Staphylococcus aureus (MRSA) and Clostridium difficile.

These antibiotics are vital for USMLE, NCLEX, GPAT, and NEET-PG due to their life-saving role, narrow spectrum, and resistance considerations.

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Stepwise Mechanism of Action of Glycopeptides

1. Binding to D-Ala-D-Ala terminus of peptidoglycan precursors
   Vancomycin binds firmly to the terminal D-Ala-D-Ala residues of nascent peptidoglycan units.
2. Inhibition of transglycosylation and transpeptidation
   This binding blocks the action of transglycosylase and transpeptidase enzymes, which are responsible for polymerizing and cross-linking the peptidoglycan chains.
3. Prevention of cell wall synthesis
   Without proper cross-linking and elongation, the bacterial cell wall becomes structurally weak.
4. Bacterial lysis and death
   The disruption causes osmotic imbalance, leading to cell lysis in actively dividing bacteria.
5. Selective Gram-positive activity
   Glycopeptides are too large to penetrate Gram-negative outer membranes, so they act only on Gram-positive bacteria.

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Pharmacokinetic Parameters of Vancomycin

Parameter	Value
Bioavailability	Very poor orally; used IV for systemic infections
Half-life	6–10 hours (longer in renal failure)
Protein binding	~50%
Metabolism	Minimal
Excretion	Renal (unchanged)
Therapeutic drug monitoring (TDM)	Required for IV use (trough levels)

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Clinical Uses of Glycopeptides

• MRSA infections (sepsis, pneumonia, endocarditis)
• Clostridium difficile colitis (oral vancomycin)
• Enterococcal infections (VSE)
• Surgical prophylaxis in penicillin-allergic patients
• Serious Gram-positive infections resistant to β-lactams

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Adverse Effects of Glycopeptides

• Red man syndrome – flushing, rash due to histamine release
• Nephrotoxicity (dose-related; increased with aminoglycosides)
• Ototoxicity (rare but serious)
• Phlebitis at injection site
• Hypersensitivity reactions
• Neutropenia (with prolonged use)

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Comparative Analysis: Vancomycin vs Teicoplanin

Feature	Vancomycin	Teicoplanin
Dosing frequency	Twice or once daily (IV)	Once daily (IV/IM)
TDM required	Yes	Not routinely
Half-life	Shorter (~6 h)	Longer (~70–100 h)
Administration route	IV/Oral (non-absorbable)	IV/IM only
Red man syndrome	Common	Rare

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Practice MCQs

Q1. Vancomycin inhibits cell wall synthesis by binding to:
a. PBPs
b. D-Ala-D-Ala terminus ✅
c. DNA gyrase
d. 30S ribosome

Q2. Vancomycin is mainly effective against:
a. Gram-negative rods
b. Mycobacteria
c. Gram-positive bacteria ✅
d. Fungi

Q3. Which adverse reaction is specific to rapid IV infusion?
a. Nephrotoxicity
b. Red man syndrome ✅
c. Photosensitivity
d. Seizures

Q4. Oral vancomycin is used to treat:
a. MRSA pneumonia
b. UTI
c. Clostridium difficile colitis ✅
d. Syphilis

Q5. Vancomycin-resistant Enterococci modify:
a. PBPs
b. D-Ala-D-Ala to D-Ala-D-Lac ✅
c. Ribosomal subunit
d. Porins

Q6. Why is vancomycin ineffective against Gram-negatives?
a. Enzymatic degradation
b. Drug efflux
c. Cannot penetrate outer membrane ✅
d. No peptidoglycan layer

Q7. Which of the following requires TDM?
a. Oral metronidazole
b. IV vancomycin ✅
c. Amoxicillin
d. Linezolid

Q8. Vancomycin acts on bacteria that are:
a. Dormant
b. Actively dividing ✅
c. Anaerobic only
d. Spore-forming

Q9. What is the common route of excretion?
a. Liver
b. Lungs
c. Renal ✅
d. Skin

Q10. What monitoring is essential during vancomycin therapy?
a. Liver enzymes
b. ECG
c. Trough plasma levels ✅
d. Pulmonary function

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FAQs

Q1: Can vancomycin be used orally for systemic infections?
No. Oral vancomycin is only for C. difficile colitis as it’s not absorbed systemically.

Q2: What causes red man syndrome?
Rapid IV infusion leads to histamine release, causing flushing and rash.

Q3: How is vancomycin dosed in renal failure?
Dosing must be adjusted and trough levels monitored due to renal excretion.

Q4: Is vancomycin safe in pregnancy?
Yes, it is Category B and can be used if needed.

Q5: What causes resistance in VRE?
Change in binding site from D-Ala-D-Ala to D-Ala-D-Lac, reducing affinity.

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References

• KD Tripathi – Essentials of Medical Pharmacology
• Goodman & Gilman – The Pharmacological Basis of Therapeutics
• Sparsh Gupta – Review of Pharmacology
• NCBI: https://www.ncbi.nlm.nih.gov/books/NBK459455/