Glycopeptide and Lipopeptide Antibiotics
Vancomycin and daptomycin target gram-positive bacteria by disrupting cell wall synthesis and membrane integrity, respectively, serving as critical agents against MRSA and VRE.
## Overview
Glycopeptides (vancomycin, teicoplanin, oritavancin) and lipopeptides (daptomycin) are critical agents against multidrug-resistant gram-positive bacteria including MRSA and VRE. They have distinct mechanisms that bypass the beta-lactam resistance of MRSA (PBP2a alteration) and have complex pharmacokinetic/pharmacodynamic characteristics requiring monitoring.
## Vancomycin: Mechanism
Vancomycin is a glycopeptide that forms hydrogen bonds with the D-Ala-D-Ala terminus of peptidoglycan precursors (lipid II), physically blocking transglycosylation (polymerization) and transpeptidation. This prevents cell wall assembly, causing osmotic lysis. Acts exclusively on gram-positive organisms (cannot penetrate the outer membrane of gram-negatives). Bactericidal against staphylococci; bacteriostatic against enterococci.
## Vancomycin Dosing: AUC/MIC Target
ASHP/IDSA/SIDP 2020 guidelines recommend AUC/MIC (24h AUC: 400-600 mg·h/L for MIC ≤1 mg/L) as the pharmacodynamic target for MRSA infections, replacing trough-only monitoring. AUC-guided dosing is associated with similar efficacy but reduced nephrotoxicity compared to trough-guided dosing. Bayesian software is used to calculate AUC from 1-2 pharmacokinetic samples.
## Vancomycin Resistance
**VRE (vancomycin-resistant enterococci)**: VanA/VanB operons reprogram cell wall synthesis to produce D-Ala-D-Lac terminus, which vancomycin binds with 1000x lower affinity. VanA: resistance to both vancomycin and teicoplanin. VanB: resistant to vancomycin only. **VISA/VRSA**: Rare staphylococcal resistance; VISA has thickened cell wall trapping vancomycin before it reaches PBPs.
## Novel Glycopeptides
**Oritavancin and dalbavancin**: Long half-lives (245h and 346h respectively) allowing single-dose therapy for ABSSSI. Oritavancin also disrupts bacterial membrane integrity.
## Daptomycin: Mechanism
Daptomycin is a lipopeptide that inserts its lipid tail into the bacterial cytoplasmic membrane in a calcium-dependent manner, causing membrane depolarization, potassium efflux, and rapid cell death. Rapid concentration-dependent bactericidal activity. Active against gram-positives including MRSA, VISA, VRE.
**Key limitation**: Inactivated by pulmonary surfactant — **NOT used for pneumonia**. Use for bacteremia, right-sided endocarditis, and skin infections.
**Resistance**: Membrane phospholipid rearrangements reduce daptomycin binding. Cross-resistance with vancomycin can occur.
## Key Takeaways
- Vancomycin blocks D-Ala-D-Ala-mediated cell wall synthesis; AUC/MIC 400-600 is the current dosing target
- VRE carries VanA/VanB genes that reprogram cell wall precursors to D-Ala-D-Lac, reducing vancomycin binding 1000-fold
- Daptomycin is inactivated by lung surfactant and must NOT be used for pneumonia
- Oritavancin and dalbavancin enable once-weekly or single-dose treatment of skin infections