Evolution of microbial resistance to vancomycin is a growing problem, in particular, within healthcare facilities such as hospitals. While newer alternatives to vancomycin exist, such as linezolid (2000) and daptomycin (2003), the widespread use of vancomycin makes resistance to the drug a significant worry, especially for individual patients if resistant infections are not quickly identified and the patient continues the ineffective treatment. Vancomycin-resistant Enterococcus  emerged in 1986. Vancomycin resistance evolved in more common pathogenic organisms during the 1990s and 2000s, including vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA). Agricultural use of avoparcin, another similar glycopeptide antibiotic, may have contributed to the evolution of vancomycin-resistant organisms.
One mechanism of resistance to vancomycin involves the alteration to the terminal amino acid residues of the NAM/NAG-peptide subunits, under normal conditions, -alanyl--alanine, to which vancomycin binds. The -alanyl--lactate variation results in the loss of one hydrogen-bonding interaction (4, as opposed to 5 for -alanyl--alanine) possible between vancomycin and the peptide. This loss of just one point of interaction results in a 1000-fold decrease in affinity. The -alanyl--serine variation causes a six-fold loss of affinity between vancomycin and the peptide, likely due to steric hindrance.
In enterococci, this modification appears to be due to the expression of an enzyme that alters the terminal residue. Three main resistance variants have been characterised to date among resistant Enterococcus faecium and E. faecalis populations:
* VanA - enterococcal resistance to vancomycin and teicoplanin; inducible on exposure to these agents
* VanB - lower-level enterococcal resistance; inducible by vancomycin, but strains may remain susceptible to teicoplanin
* VanC - least clinically important; enterococci resistant only to vancomycin; constitutive resistance
Variant of vancomycin has been tested that binds to the resistant D-lactic acid variation in vancomycin-resistant bacterial cell walls, and also binds well to the original target (vancomycin-susceptible bacteria).