Chemistry and Pharmacodynamics
Glycopeptide antibiotics (GPAs) are actinomycete-derived, glycosylated, nonribosomal peptides, which target gram-positive bacteria by inhibition of cell wall synthesis:
- Teicoplanin (not available in the United States)
Both vancomycin and teicoplanin are heptapeptides, but the carbohydrate groups of each drug differ.
Mechanism of action
- Glycopeptides are bactericidal through inhibition of cell wall synthesis in sensitive bacteria:
- The cell wall of the bacteria is strengthened by cross-linked peptidoglycan (PG) structures.
- GPAs bind to the D-alanyl-D-alanine terminus of cell wall PG precursors, causing inhibition of cell wall synthesis.
- GPAs are effective in gram-positive bacteria because PG precursors are exposed on the external surface.
- Gram-negative bacteria are not sensitive to GPAs: The lipopolysaccharide membrane is not permeable to large biomolecules.
- Teicoplanin is more potent than vancomycin.
Absorption and distribution
- Oral vancomycin and teicoplanin:
- Poor oral absorption
- Effective for intestinal infections (e.g., Clostridiodes difficile colitis), but not systemic infections
- Vancomycin is mainly administered intravenously.
- Teicoplanin is administered intravenously and intramuscularly.
- Oral vancomycin and teicoplanin:
- 30% of vancomycin is protein bound.
- Penetrates most bodily spaces (seen in bile and pleural, pericardial, synovial, and ascitic fluids)
- Reaches the cerebrospinal fluid (CSF) when the meninges are inflamed.
- Half-life is 4–6 hours.
- 90% protein bound
- Longer half-life than vancomycin (can be given as a single, daily dose)
Metabolism and excretion
- Poorly metabolized
- Excreted unchanged in the urine by the kidneys
- Teicoplanin: similar to vancomycin with primarily renal excretion
Glycopeptide antibiotics have broad activity against gram-positive bacterial infections and are often used as the last resort treatment for serious conditions.
|Teicoplanin||Similar spectrum of activity as vancomycin|
- Delayed hypersensitivity reaction:
- Immunologic mechanism
- Maculopapular rash and other cutaneous manifestations
- Red man syndrome:
- Flushing, erythema, itching of the face and chest, and sometimes hypotension resulting from histamine release caused by rapid vancomycin infusion
- Prevented by slowing infusion time and pretreating with antihistamines
- Not a true allergy
- Vancomycin-induced neutropenia:
- Rare but serious adverse reaction
- Absolute neutrophil count (ANC) < 1,000/µL (associated with prolonged use of vancomycin)
- Unknown mechanism
- Drug-induced immune thrombocytopenia:
- Not dose related
- Typically seen within 1–2 weeks of initiation
- Not dose related
- Seen in individuals with risk factors:
- Trough levels ≥ 15 mg/L or high daily doses
- Longer exposure (> 7 days)
- Preexisting renal impairment
- Concurrent administration of another nephrotoxic drug
- Manifests as tinnitus, sensorineural hearing loss, dizziness, or vertigo
- Increased risk if administered with another ototoxic agent (e.g., aminoglycosides)
- Phlebitis: inflammation, pain, swelling, and erythema of a vein from the injection of drugs or hypertonic solutions
- Generally better tolerated
- Rarely associated with incidences of red man syndrome, ototoxicity, or nephrotoxicity
- In general, hypersensitivity to vancomycin or teicoplanin
- Precautions for individuals with underlying conditions such as renal impairment, hearing disorders, neutropenia, or thrombocytopenia
Mechanism of Resistance
- Glycopeptide-resistant strains of enterococci (especially Enterococcus faecium):
- The mechanism typically involves binding with the D-alanyl-D-alanine terminus of PG precursors of the bacterial cell wall.
- Resistance results from the alteration of the D-alanyl-D-alanine target to D-alanyl-D-lactate or D-alanyl-D-serine (poor glycopeptide binding)
- Vancomycin-resistant enterococcal infections are a major source of nosocomial infection.
Comparison of Antibiotics
The following antibiotics are agents with activity against gram-positive bacteria. All act on the bacterial cell wall through varying mechanisms.
|Class of antibiotics||Mechanism of action||Drugs|
|Lipopeptides||Disruption of the bacterial cell membrane by generating an ion-conducting channel, depolarizing the membrane, and leading to cell death||Daptomycin|
|Glycopeptides||Inhibition of cell wall synthesis by binding to the D-alanyl-D-alanine terminus of cell wall peptidoglycan (PG) precursors|
|Lipoglycopeptides||Dual action of inhibition of cell wall synthesis and depolarization of the cell membrane|
Comparison of Antibiotic Coverage
Different antibiotics have varying degrees of activity against different bacteria. The table below outlines the antibiotics with activity against 3 important classes of bacteria: gram-positive cocci, gram-negative bacilli, and anaerobes.
- Bartlett, J.G., Auwaerter, P.G., Pham, P.A. (2010). The Johns Hopkins ABX Guide. Diagnosis and Treatment of Infectious Diseases. 2nd Edition. Jones & Bartlett Publishers, Sudbury MA.
- Binda, E., Marinelli, F., & Marcone, G.L. (2014). Old and New Glycopeptide Antibiotics: Action and Resistance. Antibiotics (Basel, Switzerland). 3(4), 572–594. https://doi.org/10.3390/antibiotics3040572
- Butler, M., Hansford, K., Blaskovich, M., et al. (2014). Glycopeptide antibiotics: Back to the future. J Antibiot. 67, 631–644. https://doi.org/10.1038/ja.2014.111
- Deck, D.H., Winston, L.G. (2012). Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics (Chapter 43). In Katzung, B.G., Masters, S.B., Trevor, A.J. (Eds.), Basic and Clinical Pharmacology. 12e. McGraw-Hill/Lange.
- Economou, N. J., et al. (2013). Structure of the complex between teicoplanin and a bacterial cell-wall peptide: use of a carrier-protein approach. Acta crystallographica. Section D, Biological crystallography. 69(4), 520–533. https://doi.org/10.1107/S0907444912050469
- Finch, R.G., Eliopoulos, G.M. (2005). Safety and efficacy of glycopeptide antibiotics. J Antimicrob Chemother. 55 (Suppl 2), ii5–13. https://doi.org/10.1093/jac/dki004
- MacDougall, C. (2017). Protein synthesis inhibitors and miscellaneous antibacterial agents. In Brunton L.L., et al. (Eds.), Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2189§ionid=172485211
- Patel, S., Preuss, C.V., Bernice, F. (2021). Vancomycin. StatPearls. Treasure Island (FL): StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK459263/
- Riedel, S., et al. (Eds.). (2019). Antimicrobial chemotherapy. Jawetz, Melnick, & Adelberg’s Medical Microbiology, 28e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2629§ionid=217773038
- Vancomycin: Drug information. (2021). UpToDate. Retrieved July 17, 2021, from https://www.uptodate.com/contents/vancomycin-drug-information