Due to their toxicity, use of first-generation glycopeptide antibiotics is restricted to patients who are critically ill, who have a demonstrated hypersensitivity to the β-lactams, or who are infected with β-lactam-resistant species, as in the case of methicillin-resistant Staphylococcus aureus. These antibiotics are effective principally against Gram-positive cocci.  First-generation examples exhibit a narrow spectrum of action, and are bactericidal only against the enterococci. Some tissues are not penetrated very well by glycopeptides, and they do not penetrate into the cerebrospinal fluid.
The second-generation glycopeptides, or "lipoglycopeptides", have better binding to Lipid II due to the lipophilic moieties, expanding the antibacterial spectrum. Telavancin also has a hydrophilic moiety attached to enhance tissue distribution and reduce nephrotoxicity.