New Glycopeptides

The glycopeptide antibiotics vancomycin and teichoplanin (not approved for use in the US) have been available for many years. With the increasing need for antibiotics with activity against vancomycin-nonsusceptible staphylococci and enterococci, chemical modifications to the basic glycopeptide structure have produced a series of new compounds with altered pharmacokinetics and/or enhanced activity against Gram-positive pathogens.

Oritavancin (see Figure 13.3), like vancomycin, inhibits both transglycosyl-ation and transpeptidation in bacteria by binding to the terminal D-ala-D-ala portion of the pentapeptide building blocks preventing elongation and cross-linking of pep-tidoglycan polymers during the formation of the cell wall. However, unlike vanco-mycin, oritavancin becomes a dimer and is anchored to the cell membrane by a lipophilic side chain, enhancing binding to the pentapeptide precursor. Oritavancin demonstrates concentration-dependent bactericidal activity. It is highly protein-bound (86%), which may play a role in the extended serum beta-elimination half life of 200-300 hours, allowing the antibiotic to be administered daily for 3-7 days to achieve antibiotic exposure for an entire treatment course, or to be administered once weekly. It is active against both MRSA and VRE as well as VRSA. Clinical efficacy in therapy of skin and skin structure infections has been shown to be equivalent to vancomycin. The side effect profile is also statistically equivalent to vancomycin from data presented to date (Bhavnani et al., 2004; Guay, 2004).

Dalbavancin (see Figure 13.4) displays many characteristics of the other gly-copeptides in the inhibition of transglycosylation (and indirectly, transpeptidation), but appears to exert additional antibiotic effects similar to that of the lipopeptides in destabilizing the bacterial cell membrane, providing some degree of dual mechanism activity. The dalbavancin is active against staphylococci, including methicillin-resistant strains, as well as streptococci. With respect to enterococci, however, E. faecalis stains which carry the vanA resistance genes are not susceptible, in contrast to E. faecium strains which carry the vanB resistance determinant. The antibiotic demonstrates concentration-dependent bactericidal activity, is highly protein-bound (98%) with a prolonged serum beta half life of 257 hours using a

Figure 13.3. Oritavancin.
Figure 13.4. Dalbavancin.

renal excretion pathway of drug elimination. Dosing for skin and skin structure infections in adults has occurred once weekly in current clinical trials. Safety assessments in phase 2 trials suggest an equivalent profile to vancomycin, but patient numbers are too small for statistically valid conclusions. Dalbavancin may be useful in the therapy of MRSA and some strains of VRE, and weekly parenteral therapy will be of great value in facilitating outpatient parenteral therapy of serious infections (Leighton et al., 2004; Raad et al., 2005; Seltzer et al., 2003; Streit et al., 2005).

Telavancin (see Figure 13.5) also displays multiple mechanisms of action, including both inhibition of transglycosylation in cell wall synthesis, as well as destabilization of the bacterial cell membrane. The activity of telavancin is also similar to other extended spectrum glycopeptides in that it includes virtually all strains of MRSA, VRSA, VRE, as well as strains of pneumococcus. Telavancin exhibits concentration-dependent bactericidal activity, with a serum half-life of 7-9 hours which justified once daily dosing in clinical trials. In limited adult studies of skin and skin structure infection, telavancin was as effective as comparators, with fewer side effects compared to vancomycin. The histamine-release side effects seen with more rapid infusions of vancomycin were also noted with telavancin. As with the other new glycopeptides, telavancin may offer an effective and safe alternative to vancomycin in the treatment of multiply-resistant Gram positive pathogens (Hegde et al., 2004; Higgins et al., 2005; King et al., 2004; Shaw et al., 2005; Stryjewski et al., 2005).

Figure 13.5. Telavancin.

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