Glycopeptides

The glycopeptide antibiotics (GPAs) vancomycin and teicoplanin are inhibitors of bacterial cell wall synthesis and considered the last resort treatment of severe infections due to gram-positive bacteria such as Staphylococcus aureus, Enterococcus spp., and Clostridiodes difficile. Vancomycin is the only GPA available in the United States. The medication has poor absorption in the GI tract; therefore, oral vancomycin is used for infections of the intestinal lumen including C. difficile. Intravenous vancomycin is indicated for severe gram-positive infections including endocarditis, pneumonia, and bacteremia. Significant adverse effects include anaphylaxis, hypersensitivity reactions, red man syndrome (related to rapid infusion), nephrotoxicity, and ototoxicity.

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Chemistry and Pharmacodynamics

Definition

Glycopeptide antibiotics (GPAs) are actinomycete-derived, glycosylated, nonribosomal peptides, which target gram-positive bacteria by inhibition of cell wall synthesis:

  • Vancomycin
  • Teicoplanin (not available in the United States)

Chemical structure

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.
Mechanism of action vancomycin

Mechanism of action:
Vancomycin interferes with the normal incorporation of peptidoglycan precursors.
The bottom row shows vancomycin resistance:
Synthesis of D-alanyl-D-lactate precursors in the cell wall bind poorly with vancomycin, which reduces the effectivity of the antibiotic.

Image by Lecturio. License: CC BY-NC-SA 4.0

Pharmacokinetics

Absorption and distribution

  • Absorption:
    • 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.
  • Distribution:
    • Vancomycin:
      • 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.
    • Teicoplanin:
      • 90% protein bound
      • Longer half-life than vancomycin (can be given as a single, daily dose)

Metabolism and excretion

  •  Vancomycin:
    • Poorly metabolized
    • Excreted unchanged in the urine by the kidneys
  • Teicoplanin: similar to vancomycin with primarily renal excretion

Indications

Glycopeptide antibiotics have broad activity against gram-positive bacterial infections and are often used as the last resort treatment for serious conditions. 

Table: Indications for glycopeptide antibiotics
DrugIndicationsClinical Pearls
Vancomycin
  • Clostridiodes difficile infection (oral)
  • Staphylococcal infections:
    • Bacteremia
    • Bone infections
    • Lower respiratory tract infections (pneumonia)
    • Skin and soft tissue infections (SSTIs)
    • Meningitis/central nervous system infections
  • Endocarditis:
    • Enterococcus
    • Corynebacteria
    • Staphylococci (including MRSA)
    • Streptococcus viridans
    • Streptococcus bovis
  • Does not cover gram-negative organisms
  • Intravenous infusion is administered over 60 minutes (rapid infusion → red man syndrome)
  • Vancomycin monitoring:
    • Serum trough levels (within 30 minutes prior to a dose, typically before the 4th dose of a regimen)
    • Renal function (dose adjustment may be needed if function is impaired)
    • CBC (depending on underlying condition or adverse effect)
TeicoplaninSimilar spectrum of activity as vancomycin
  • Better tolerated than vancomycin
  • Not available in the United States

Adverse Effects

Vancomycin

  • Anaphylaxis
  • 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
  • Nephrotoxicity:
    • 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
  • Ototoxicity:
    • 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

Teicoplanin

  • Generally better tolerated
  • Rarely associated with incidences of red man syndrome, ototoxicity, or nephrotoxicity

Contraindications

  • 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.

Table: Comparison of antibiotics
Class of antibioticsMechanism of actionDrugs
LipopeptidesDisruption of the bacterial cell membrane by generating an ion-conducting channel, depolarizing the membrane, and leading to cell deathDaptomycin
GlycopeptidesInhibition of cell wall synthesis by binding to the D-alanyl-D-alanine terminus of cell wall peptidoglycan (PG) precursors
  • Vancomycin
  • Teicoplanin
LipoglycopeptidesDual action of inhibition of cell wall synthesis and depolarization of the cell membrane
  • Telavancin
  • Dalbavancin
  • Oritavancin

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.

Antibiotic sensitivity chart

Antibiotic sensitivity:
Chart comparing the microbial coverage of different antibiotics for gram-positive cocci, gram-negative bacilli, and anaerobes.

Image by Lecturio. License: CC BY-NC-SA 4.0

References

  1. 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.
  2. 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
  3. 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
  4. 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.
  5. 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
  6. 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
  7. 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&sectionid=172485211
  8. Patel, S., Preuss, C.V., Bernice, F. (2021). Vancomycin. StatPearls. Treasure Island (FL): StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK459263/
  9. 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&sectionid=217773038
  10. Vancomycin: Drug information. (2021). UpToDate. Retrieved July 17, 2021, from https://www.uptodate.com/contents/vancomycin-drug-information

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