Glycopeptide antibiotics act primarily by inhibiting cell wall synthesis of bacteria but functions differently from beta-lactam antibiotics. Vancomycin is the most important and commonly used glycopeptides, although teicoplanin is also available. Glycopeptides are active against most gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA).
Most Gram-negative bacteria are intrinsically resistant to vancomycin because their outer membranes are impermeable to large glycopeptide molecule.
DO YOU KNOW?
Vancomycin was isolated by E.C. Kornfeld and colleagues; scientists working at Eli Lilly in 1953 from a soil sample obtained in the jungle of Borneo. Vancomycin is a fermentation product of an actinomycete Streptomyces orientalis (which was later renamed Amycolatopsis orientalis). Initially the compound (compound 05865) isolated from the organism was also dubbed “Mississippi mud” because of its brown color and was later renamed vancomycin (from the word “vanquish”)
Glycopeptide antibiotics (vancomycin, teicoplanin) contain two sugars and an aglycone moiety made of a relatively highly conserved heptapeptide core, bearing two chloride substituents.
The aglycone fraction is responsible for the pharmacologic activity of the molecule, whereas the sugars modulate its hydrophilicity and its propensity to form dimers.
Lipoglycopeptides (dalbavancin, oritavancin, and telavancin) are semisynthetic derivatives characterized by the addition of a hydrophobic moiety, which confers additional properties to the drugs.
Mechanism of Action
Vancomycin does not bind to penicillin-binding proteins (PBPs) but does bind to precursors of cell wall synthesis. The binding interferes with the ability of the PBP enzymes, such as transpeptidases and tranglycosylases, to incorporate the precursors into the growing cell wall.
Vancomycin binds to the D-Ala-D-Ala terminal of the growing peptide chain during cell wall synthesis resulting in inhibition of the transpeptidase, which prevents further elongation and cross-linking of the peptidoglycan matrix.
Vancomycin also inhibits transglycosylase (glycosyltransferase), a second enzyme responsible for cross-linking sugar residues. The mechanism for transglycosylase inhibition is unclear. With the cessation of cell wall synthesis, cell growth stops and death often follows.
Use against Gram-Positive Bacteria
Glycopeptide antibiotics are believed to represent the last line of defense against the often lethal Gram-positive bacterial infections. Vancomycin remains the first-line drug against methicillin-resistant Staphylococcus aureus (MRSA); however, the emergence of resistance in enterococci and staphylococci has led to a restriction in the use of vancomycin as well as teicoplanin.
Use against Gram-Negative Bacteria
Because of its relatively large size, vancomycin cannot penetrate the outer membrane of most gram-negative bacteria to reach their cell wall precursor targets. Therefore, this agent is usually ineffective against gram-negative bacteria.
Resistance to Vancomycin
Vancomycin-resistant enterococcus (VRE) were reported in Europe by 1986 and in the United States by 1987. Six resistance patterns (designated “VanA” through “VanE,” and, most recently, “VanG”) have been reported. Multiple genes are responsible for these different phenotypes, but they produce resistance by only one or the other of 2 common pathways.
The target for vancomycin is the terminal d-alanyl-d-alanine of the growing peptidoglycan chain. In vancomycin-resistant organisms, these peptidoglycan intermediates are altered to either d-alanyl-d-lactate (VanA, VanB, and VanD) or d-alanyl-d-serine (VanC, VanE, and VanG). These altered targets have a reduced affinity for vancomycin, resulting in much higher minimum inhibitory concentrations (MICs).
Table 1: Classification of Staphylococus aureus on the basis of vancomycin susceptibility
|Isolates||Minimal Inhibitory Concentration (MIC)|
|Vancomycin-susceptible S.aureus||0.5-2 μg/mL|
|Vancomycin-intermediate S.aureus (VISA)||4-8 μg/mL|
|Vancomycin-resistant S.aureus (VRSA)||≥16 μg/mL|
All VRSA isolates to date contained the vanA vancomycin resistance gene. Most VRSA-positive patients had a history of infections caused by both VRE containing vanA and MRSA. It is likely that the vanA determinant was transferred via plasmids or transposons from the VRE to the MRSA strain, resulting in the VRSA.
Susceptibility Test for Vancomycin
CLSI recommends performing MIC tests to determine the susceptibility of staphylococci to vancomycin. Not all susceptibility testing methods detect VISA and VRSA isolates. The disk test does not differentiate vancomycin-susceptible isolates of S. aureus from vancomycin-intermediate strains. Non-automated MIC methods can detect both VRSA and VISA isolates.
Table 2: Methods used for the detection of VRSA and VISA are tabulated below:
|Method||Detection of VRSA||Detection of VISA|
| Vancomycin screen agar plate |
(contains BHI agar and 6 µg/ml of vancomycin)
|Yes||Detects isolates having MICs >8 µg/ml|
|MicroScan® overnight and Synergies plus™,||Yes||No|
|BD Phoenix™ system||Yes||No|
References and further reading
- CDC: Laboratory Detection of Vancomycin-Intermediate/Resistant Staphylococcus aureus (VISA/VRSA)
- Donald P. Levine: Vancomycin: A History, Department of Medicine, Wayne State University, Detroit, Michigan
- Schafer, M. et al. (1996) Crystal structure of vancomycin. Structure 4, 1509-1515.