Resistance in the Glycopeptide Antimicrobial Class


A number of gram positive bacterial species are intrinsically resistant to vancomycin and teicoplanin. These include Leuconostoc, Pediococcus, Nocardia, Lactobacillus, and Erysipelothrix. In these species the cell wall structure does not permit binding of these agents to the growing peptides in the wall.

The most extensively studied resistance phenomenon has been in the enterococci. Resistance to vancomycin and teichoplanin has been shown to result from synthesis of modified precursor molecules with lower affinity for these compounds.  Six types of resistance have been reported; van A, B, C, D, E, and G. The most common mechanisms observed in clinical strains of enterococci are van A, B, and C.

Van A high-level resistance occurs most commonly in Enterococcus faecium (MICs of > 1000 mg/L) and less often in Enterococcus faecalis. At the cell wall level the bacteria are able to replace the D-ala-D-ala peptide with D-ala-D-lac. This results in a loss of a critical hydrogen bond for vancomycin and resistance functionally is complete. The resistance genes are carried on a transposon that encodes genes for seven polypeptides which are involved in the development of resistance. van R and S regulate gene expression for resistance. van H, A and X confer resistance to vancomcyin and teicoplanin; van Y and Z are accessory proteins that are not directly involved in resistance. van X (a dipeptidase), is required for complete resistance and van Y (a carboxypeptidase) is capable of cleaving late cell wall development by cleaving D-ala in those cells. The mechanism for van Z involvement is not completely known.  This high level resistance is inducible by vancomycin. It is plasmid mediated and transferable.

Van B resistance is lower level (MICs 8 – 64 mg/L), occurs in both E. faecium and E. faecalis and  confers resistance to vancomycin but not teicoplanin.  Van B determinants are also found on transposons both on plasmids and chromosomally. Mutations that arise in the van gene clusters in enterococci in these strains results in impaired phosphorylation of van R and S and result in the low and variable MICs observed in these strains.

Van C resistance occurs in E. gallinarum, E. cassiliflaveus and E. flavescens. These species are intrinsically resistant to low concentrations of vancomycin, but are susceptible to teicoplanin. For these species, three genes, van C-1, van C-2 and van C have been described. These genes are constitutively expressed and chromosomally encoded. They are not transferable on plasmids, and therefore are not a concern from the infection prevention and control perspective.

The derivative glycopeptides have different mechanisms of activity (e.g., oritavancin acts on lipid formation and transglycosylation instead of peptide formation). In this way, for example vancomycin-resistant enterococci remain susceptible to these compounds with MICs of ≤ 1-2 mg/. For Van A resistant E. faecium (MICs> 256 mg/L) the MIC90 for oritavancin is 0.25 mg/L.

Resistance to vancomycin has also been observed in S. aureus, primarily in methicillin-resistant strains (MRSA). MRSA strains with decreased susceptibility to vancomycin (vancomycin intermediate-resistant S. aureus (VISA or GISA) and more recently with high-level vancomycin resistance (vancomycin-resistant S. aureus (VRSA) have been described in the clinical literature. The rare VRSA strains carry transposon Tn1546, acquired from vancomycin-resistant E. faecalis, which is known to alter cell wall structure and metabolism, but the resistance mechanisms in GISA isolates are less well defined. These strains are described as hetero-resistant. Decreased susceptibility is induced in the presence of vancomycin, and teichoic acid in the cell wall of these isolates increases. The thicker cell wall (clearly observed by electron microscopy) results in reduced affinity of vancomycin for the growing cell wall and an increase in MIC to 4 – 8 mg/L. True VRSA strains have high MICs > 16 – 32 mg/L. (2,3).  These MRSA strains have remained susceptible to newer derivative glycopeptides.

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