Glycopeptide antibiotics: evolving resistance, pharmacology and adverse event profile

Abstract

The first glycopeptide antibiotic was vancomycin, isolated from the soil in the 1950s; since then, the class has expanded to include teicoplanin and the new semisynthetic glycopeptides dalbavancin, oritavancin and telavancin. They are bactericidal, active against most Gram-positive organisms, and in a concentration-dependent manner, inhibit cell wall synthesis. Resistance to vancomycin has emerged, especially among enterococci and Staphylococcus aureus through a variety of mechanisms. This emerging resistance to vancomycin makes proper dosing and monitoring of the area under the curve/MIC critically important. The chief adverse effect of vancomycin is nephrotoxicity, which is also intricately related to its dose. The efficacy of the semisynthetic glycopeptides has been demonstrated in skin and soft-tissue infections, but remains to be seen in serious methicillin-resistant Staphylococcus aureus infections.

Keywords:

• adverse events
• dalbavancin
• glycopeptides
• oritavancin
• pharmacodynamics
• pharmacokinetics
• teicoplanin
• telavancin
• vancomycin

Financial & competing interests disclosure

DP Levine has received research support from Cerexa, Forest Laboratories, Cubist and AstraZeneca, is an advisor to Theravance, Cerexa, Cubist, Forest Laboratories and Melinta Therpeutics, and has been on the speakers’ bureau for Cubist, Theravance and Forest Laboratories. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• The need for antibiotics that are active against increasingly resistant Gram-positive bacteria is an important impetus for the development of new glycopeptide antibiotics (GPAs) with better pharmacokinetic and toxicologic profiles.

• The GPAs are tricyclic or tetracyclic compounds with a core of seven amino acids (heptapeptide) to which are bound two sugar moieties. The lipoglycopeptides have, in addition, lipophilic side chains that increase interaction with the bacterial cell membrane. There are currently five GPAs in wide clinical use today: vancomycin, teicoplanin (in Europe), dalbavancin, oritavancin and telavancin.

• The GPAs inhibit cell wall synthesis and act by binding to the C-terminal D-Ala-D-Ala of peptidoglycan precursors, preventing these precursors from participating in further synthesis of the bacterial cell wall.

• Vancomycin-resistant Staphylococcus aureus (VRSA) developed after resistance genes (vanA and vanB) were acquired from enterococci. VRSA, known as a high-level resistance to vancomycin, took 30 years to develop and to date, only 13 strains have been reported worldwide.

• Vancomycin-intermediate strains (VISA) develop from vancomycin-susceptible (VSSA) strains after prolonged infection and exposure to vancomycin. This low-level GPA resistance is more common than VRSA.

• Heterogeneous vancomycin-intermediate S. aureus (hVISA) is defined as an isolate with a vancomycin MIC in the susceptible range but where a proportion of the cells have MICs in the intermediate range. This poses a challenge for clinicians; the most common presentation is clinical failure while on vancomycin therapy.

• A good understanding of vancomycin pharmacodynamics is essential to avoid the development of resistant bacteria. The best predictor of vancomycin efficacy is an area under the curve/MIC of ≥400. Achieving such high area under the curve/MIC ratios is problematic, particularly if the infecting strain’s MIC is ≥1 μg/ml. This problem is further compounded by the presence of renal insufficiency when higher doses of vancomycin may lead to worsening renal function.

• The lipoglycopeptides (dalbavancin, telavancin and oritavancin), approved for the use in skin and soft tissue infections, are more rapidly bactericidal when compared with vancomycin. The best predictor of efficacy in this subclass is also the area under the curve/MIC. Because of their lipophilic side chains, these compounds have very long half-lives. Oritavancin, for example, can be given as a single dose to treat skin and soft tissue infections. These have no oral formulation and are more highly protein bound.

• Among the adverse effects associated with vancomycin, nephrotoxicity is dependent on dose and duration of therapy, while neutropenia is dependent on duration of therapy. The adverse effects are generally reversible with discontinuation of therapy.

• The newer lipoglycopeptides, specifically dalbavancin and oritavancin, as well as the glycopeptide teicoplanin have less adverse effects compared with vancomycin.

Notes