Lipopeptides and Lipoglycopeptides

Lipopeptides and lipoglycopeptides are classes of antibiotics that have activity against gram-positive bacteria and that act on the bacterial cell wall. Lipopeptides (daptomycin) disrupt the cell membrane by creating an ion-conducting channel and causing potassium efflux and membrane depolarization. The subsequent processes lead to inhibited protein synthesis and eventual bacterial cell death. Lipoglycopeptides have a dual action of inhibiting bacterial cell-wall synthesis by binding peptidoglycan precursors and causing cell membrane depolarization. Telavancin, dalbavancin, and oritavancin belong to this group of drugs. All these medications are administered IV, as they have poor oral absorption. The lipopeptides and lipoglycopeptides are excreted unchanged in the urine. Dosage adjustments are generally needed in cases of reduced renal function. Both classes of antibiotics are used as alternative agents for gram-positive infections (bacteremia, skin and soft tissue infections). Telavancin is also effective against hospital-acquired and ventilator-associated pneumonia.

Last update:

Table of Contents

Share this concept:

Share on facebook
Share on twitter
Share on linkedin
Share on reddit
Share on email
Share on whatsapp

Chemistry and Pharmacodynamics

Lipopeptides

  • Daptomycin: only member of its class
  • Structure: 
    • 13 amino acids, with 10 forming an ester-linked amino acid ring
    • With a terminal L-tryptophan bonded to decanoic acid
Chemical structure of daptomycin

Chemical structure of daptomycin

Image: “Daptomycin Ball et al.” by Fvasconcellos. License: Public Domain

Mechanism of action of lipopeptides

  • Bactericidal (concentration-dependent killing): 
    • Lipophilic tail binds to bacterial membranes (calcium-dependent) → creates a hole or channel in the membrane, causing potassium ions to leak out
    • Rapid depolarization → loss of membrane potential → inhibition of proteins, RNA and DNA synthesis
    • Processes initiated lead to cell death.
  • Activity only against gram-positive bacteria
Mechanism of action daptomycin

Mechanism of action:
Daptomycin binds to the bacterial cell membrane, and holes are created in the membrane by altering the shape of the membrane. Potassium ion leaks out of the membrane, and rapid depolarization occurs. There is loss of ion gradient, which eventually leads to inhibition of protein synthesis, effectively resulting in cell death.
DAP: daptomycin

Image: “Multifunctional pharmaceutical effects of the antibiotic daptomycin” by Yang Ye et al. License: CC BY 4.0, cropped by Lecturio.

Lipoglycopeptides

  • Semisynthetic derivatives of glycopeptides (e.g., vancomycin)
  • Contains lipophilic side chains (that vary depending on the compound) attached to the glycopeptide, prolonging the half-life
  • Activity against gram-positive bacteria
  • Includes: 
    • Telavancin: derivative of vancomycin
    • Dalbavancin: teicoplanin-like molecule
    • Oritavancin

Mechanism of action of lipoglycopeptides

  • Lipoglycopeptides are bactericidal, demonstrating concentration-dependent killing.
  • Dual actions:
    • Have increased binding to the D-alanyl-D-alanine terminus of cell-wall peptidoglycan precursors (similar to glycopeptides, but with improved potency):
      • Block peptidoglycan polymerization 
      • Inhibit cell-wall synthesis
    • Cause direct disruption of the bacterial cell membrane, causing depolarization, increased permeability and cell death (similar to lipopeptides)
  • Oritavancin also inhibits RNA synthesis.

Pharmacokinetics

Lipopeptides: daptomycin

  • Absorption and distribution:
    • Poor oral absorption, and toxic to the muscle (cannot give IM) → only administered IV 
    • Serum half-life: 8–9 hours
    • Highly protein-bound, with different organ pharmacokinetics:
      • Good skin and soft tissue penetration
      • Urinary tract: Daptomycin is excreted unchanged in the urine, so it is an option for complicated urinary tract infections.
      • Respiratory tract: Daptomycin is inactivated by pulmonary surfactant, so it is not useful for pneumonia.
      • CNS: poor penetration of CSF even with inflammation
  • Metabolism and excretion:
    • Excreted renally as an active drug 
    • Dose adjustments needed for creatinine clearance < 30 mL/min

Lipoglycopeptides

  • Telavancin: 
    • Absorption and distribution:
      • Not absorbed orally
      • Highly protein-bound
      • Serum half-life: 7–8 hours
      • Adequate concentration in skin and soft tissues and lung tissue (thus, used in pneumonia and skin and soft tissue infections)
    • Metabolism and excretion:
      • Minimal metabolism
      • Primarily excreted in the urine
      • Dose adjustment needed for creatinine clearance < 50 mL/min
  • Dalbavancin:
    • Absorption and distribution:
      • Not absorbed orally
      • Highly protein-bound
      • Long half-life (allowing 1- or 2-dose regimen)
      • Good penetration of skin and bone tissues, but poor CSF penetration
    • Metabolism and excretion:
      • Eliminated unchanged in the urine
      • Dose adjustment needed for creatinine clearance < 30 mL/min
  • Oritavancin:
    • Absorption and distribution:
      • Not absorbed orally
      • Highly protein-bound
      • Long half-life (allowing single dose as treatment)
    • Metabolism and excretion:
      • No hepatic metabolism
      • Excreted slowly in the urine 
      • No dose adjustment for mild to moderate renal impairment

Indications

Lipopeptides and lipoglycopeptides are agents active against gram-positive bacteria.

Lipopeptides: daptomycin (IV)

  • Treatment of gram-positive infections in which there is intolerance to standard therapy or antibiotic resistance is present:
    • Staphylococcus aureus bacteremia (bloodstream infections):
      • Includes MRSA
      • Includes right-sided endocarditis 
    • Complicated skin and soft tissue infections (SSTIs):
      • Approved for vancomycin-sensitive Enterococcus (VSE)
      • Likely with activity against vancomycin-resistant Enterococcus (VRE), but studies are insufficient for FDA approval.
  • Important note: not for pneumonia because lung surfactant inactivates the drug

Lipoglycopeptides

  • Telavancin (IV):
    • Alternative agent for complicated SSTIs due to gram-positive bacteria, including MRSA and VSE
    • Hospital-acquired and ventilator-associated pneumonia
  • Dalbavancin (IV): acute bacterial skin and skin structure infections (ABSSSI) due to gram-positive bacteria, including MRSA and VSE
  • Oritavancin (IV):
    • ABSSSI:
      • Gram-positive pathogens, including MRSA and VSE
      • In vitro activity against VRE but no trial data
    • An alternative agent, used for individuals who cannot receive 1st-line agents

Adverse Effects and Contraindications

Lipopeptides: daptomycin

  • Adverse effects include (but not limited to):
    • Myopathy/rhabdomyolysis:
      • Monitor for muscle pain/weakness.
      • CK monitoring
      • More frequent monitoring important in those with renal dysfunction and/or taking statins
    • Eosinophilic pneumonia:
      • Occurs 2–4 weeks after initiation of therapy
      • Presents as new-onset fever and infiltrate on chest X-ray
    • Anaphylactic hypersensitivity reactions
    • Peripheral neuropathy
    • Can falsely ↑ prothrombin time and INR
  • Contraindication: hypersensitivity to daptomycin or its components

Lipoglycopeptides

  • Telavancin:
    • Adverse effects include (but not limited to):
      • Renal dysfunction or nephrotoxicity, foamy urine
      • Rapid infusion can cause vancomycin flushing syndrome (VFS; previously known as red man syndrome), which consists of flushing, erythema, itching, and hypotension from histamine release, as with vancomycin
      • QT prolongation
      • Embryofetal toxicity (need to verify pregnancy)
      • Taste disturbance (metallic), nausea, vomiting
      • May interfere with coagulation studies
    • Contraindications:
      • Hypersensitivity to telavancin or its components
      • Concomitant use of unfractionated heparin
  • Dalbavancin:
    •  Adverse effects include (but not limited to):
      • GI intolerance (nausea, diarrhea, constipation) 
      • Transaminitis
      • Hypokalemia
      • Hypotension
    • Contraindication: hypersensitivity to dalbavancin or its components
  • Oritavancin:
    • Adverse effects include (but not limited to):
      • Nausea, vomiting
      • Infusion-related reactions
      • May interfere with coagulation studies
    • Contraindications:
      • Hypersensitivity to oritavancin or its components
      • Concomitant use of unfractionated heparin (≤ 5 days after oritavancin administration)

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. Abbott, I., Cairns, K. (2021). Daptomycin: an overview. UpToDate. Retrieved July 18, 2021, from https://www.uptodate.com/contents/daptomycin-an-overview
  2. Binda, E., Marinelli, F., Marcone, G.L. (2014). Old and new glycopeptide antibiotics: action and resistance. Antibiotics 3:572–594. https://doi.org/10.3390/antibiotics3040572
  3. Dalbavancin: drug information. (2021). UpToDate. Retrieved July 18, 2021, from https://www.uptodate.com/contents/dalbavancin-drug-information
  4. Daptomycin: drug information. (2021). UpToDate. Retrieved July 18, 2021, from https://www.uptodate.com/contents/daptomycin-drug-information
  5. Damodaran, S.E., Madhan, S. (2011). Telavancin: a novel lipoglycopeptide antibiotic. Journal of Pharmacology & Pharmacotherapeutics 2(2):135–137. https://doi.org/10.4103/0976-500X.81918
  6. MacDougall, C. (2017). Protein synthesis inhibitors and miscellaneous antibacterial agents. Chapter 59 of Brunton L.L., Hilal-Dandan, R., Knollmann, B.C. (Eds.), Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13th ed. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2189&sectionid=172485211
  7. Murray, B., Miller, W. (2021). Treatment of enterococcal infections. UpToDate. Retrieved July 18, 2021, from https://www.uptodate.com/contents/treatment-of-enterococcal-infections
  8. Oritavancin: Drug information. (2021). UpToDate. Retrieved July 18, 2021, from https://www.uptodate.com/contents/oritavancin-drug-information
  9. Patel, S., Saw S. (2021). Daptomycin. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK470407/
  10. Riedel, S., et al. (Eds.). (2019). Antimicrobial chemotherapy. Chapter 28 of Jawetz, Melnick, & Adelberg’s Medical Microbiology, 28th ed. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2629&sectionid=217773038
  11. Rosenthal, S., et al. (2018). Oritavancin (Orbactiv): a new-generation lipoglycopeptide for the treatment of acute bacterial skin and skin structure infections. P T 43:143–179. https://pubmed.ncbi.nlm.nih.gov/29491695/
  12. Telavancin: drug information. (2021). UpToDate. Retrieved July 18, 2021, from https://www.uptodate.com/contents/telavancin-drug-information

Study on the Go

Lecturio Medical complements your studies with evidence-based learning strategies, video lectures, quiz questions, and more – all combined in one easy-to-use resource.

Learn even more with Lecturio:

Complement your med school studies with Lecturio’s all-in-one study companion, delivered with evidence-based learning strategies.

🍪 Lecturio is using cookies to improve your user experience. By continuing use of our service you agree upon our Data Privacy Statement.

Details