Glycopeptides

GLYCOPEPTIDES  

The only two important glycopeptide antibiotics currently available are vancomycin and teicoplanin. Like many of the other antibiotics in current use, vancomycin is a relatively old drug, having been introduced in 1958, but its activity against MRSA resulted in it becoming progressively more valuable as MRSA became more prevalent. It has a complex tricyclic glycopeptide structure and its large molecular size means that it cannot penetrate through the outer membrane of most Gram-negative bacteria, so its use is effectively restricted to the treatment of infections by aerobic or anaerobic Gram-positive species. In addition to Staph. aureus, it is active against Staph. epidermidis, streptococci, Cl. difficile and Ent. faecalis, although resistant enterococci are posing an increasing clinical problem.

Vancomycin is bactericidal to most susceptible bacteria at concentrations near its minimum inhibitory concentration (MIC) and is an inhibitor of bacterial cell wall peptidoglycan synthesis, although at a site different from that of β-lactam antibiotics. Employed as the hydrochloride and administered by dilute intravenous injection, vancomycin is indicated in potentially life-threatening infections that cannot be treated with other, less toxic, antibiotics. Oral vancomycin, which is not absorbed from the gastrointestinal tract, is the drug of choice in the treatment of antibiotic-induced pseudo-membranous colitis associated with the administration of antibiotics such as clindamycin and lincomycin. Although not chemically related to the aminoglycosides, vancomycin suffers the same toxicity problems and has the potential to damage both the kidney and the ears, and it too is normally subject to blood-level monitoring during therapy.

Because of its potential toxicity, its poor penetration of bile and cerebrospinal fluid, the requirement for twice-daily dosing, and pain on intramuscular administration that effectively limits vancomycin to the intravenous route, there was scope for the introduction of a second glycopeptide antibiotic in which these deficiencies were eliminated or reduced; accordingly, teicoplanin was marketed in Europe in the early 1990s. Teicoplanin has the same mode of action and antimicrobial spectrum as vancomycin, as well as a similar chemical structure, but, crucially, teicoplanin possesses more fatty acid side chains which make the molecule more acidic, thereby permitting the formulation of a sodium salt that can be given both by intravenous and intramuscular injection, and  make teicoplanin more lipophilic, which affords better tissue penetration and a longer half-life; as a consequence, teicoplanin is normally administered once daily rather than twice. Other advantages over vancomycin are a slightly higher potency against most target organisms and a better toxicity profile, thereby eliminating the need for routine blood monitoring.