Mechanism of Action of Daptomycin

Introduction

Daptomycin is a cyclic lipopeptide antibiotic with potent activity against Gram-positive bacteria, including multidrug-resistant organisms such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). It has a unique mechanism of action distinct from cell wall synthesis or protein synthesis inhibition, making it a high-yield topic in pharmacology, microbiology, and infectious disease examinations. Daptomycin is bactericidal and is reserved for serious systemic infections.

Mechanism of Action (Step-wise)

Daptomycin causes rapid bacterial cell death by disrupting the cell membrane potential.

Step-wise mechanism:

1. Calcium-Dependent Binding
   Daptomycin binds to bacterial cell membranes in the presence of calcium ions (Ca²⁺).
2. Insertion into Gram-Positive Cell Membrane
   The lipophilic tail of daptomycin inserts into the cytoplasmic membrane of Gram-positive bacteria.
3. Oligomerization and Channel Formation
   Multiple daptomycin molecules aggregate to form transmembrane complexes.
4. Membrane Depolarization
   These complexes create ion-conducting channels that allow potassium efflux.
5. Loss of Membrane Potential
   Rapid depolarization of the bacterial membrane occurs.
6. Inhibition of Macromolecular Synthesis
   Loss of membrane potential inhibits:
   • DNA synthesis
   • RNA synthesis
   • Protein synthesis
7. Rapid Bactericidal Effect
   The bacteria undergo cell death without cell lysis, reducing inflammatory response.

Pharmacokinetics

• Administration: Intravenous only
• Absorption: Not absorbed orally
• Distribution: Widely distributed; poor penetration into lungs
• Protein binding: High (~90%)
• Metabolism: Minimal hepatic metabolism
• Elimination: Renal excretion (dose adjustment required)
• Half-life: Approximately 8–9 hours

Important note:
Daptomycin is inactivated by pulmonary surfactant and therefore cannot be used for pneumonia.

Clinical Uses

Daptomycin is indicated for serious Gram-positive infections:

• Complicated skin and soft tissue infections
• MRSA bacteremia
• Right-sided infective endocarditis
• Vancomycin-resistant Enterococcus infections
• Severe Gram-positive infections resistant to other agents

Adverse Effects

Key adverse effects include:

• Musculoskeletal:
  • Myopathy
  • Elevated creatine phosphokinase (CPK)
• Neurologic:
  • Peripheral neuropathy (rare)
• Gastrointestinal:
  • Nausea
  • Diarrhea
• Others:
  • Eosinophilic pneumonia (rare but serious)

Monitoring:
Baseline and weekly CPK levels are recommended, especially when used with statins.

Comparative Analysis (must include a table + explanation)

Comparison of Anti–Gram-Positive Antibiotics

Explanation:
Daptomycin is unique among antibiotics because it kills bacteria by disrupting membrane potential rather than inhibiting synthesis pathways. However, its inactivation by surfactant limits its use in pulmonary infections, where vancomycin or linezolid are preferred.

MCQs (10–15)

1. Daptomycin kills bacteria primarily by:
   a) Inhibiting cell wall synthesis
   b) Inhibiting protein synthesis
   c) Depolarizing cell membrane
   d) Inhibiting DNA gyrase

Answer: c) Depolarizing cell membrane

2. Daptomycin requires which ion for activity?
   a) Sodium
   b) Potassium
   c) Calcium
   d) Magnesium

Answer: c) Calcium

3. Daptomycin is bactericidal because it:
   a) Causes cell lysis
   b) Inhibits peptidoglycan synthesis
   c) Causes membrane depolarization
   d) Inhibits ribosomal translocation

Answer: c) Causes membrane depolarization

4. Daptomycin is ineffective in pneumonia because it is:
   a) Rapidly metabolized
   b) Inactivated by surfactant
   c) Poorly absorbed
   d) Nephrotoxic

Answer: b) Inactivated by surfactant

5. Which organism is covered by daptomycin?
   a) Escherichia coli
   b) Pseudomonas aeruginosa
   c) Enterococcus faecium (VRE)
   d) Mycoplasma pneumoniae

Answer: c) Enterococcus faecium (VRE)

6. Daptomycin is administered by which route?
   a) Oral
   b) Intramuscular
   c) Intravenous
   d) Subcutaneous

Answer: c) Intravenous

7. A major adverse effect of daptomycin is:
   a) Nephrotoxicity
   b) Ototoxicity
   c) Myopathy
   d) QT prolongation

Answer: c) Myopathy

8. Which lab parameter should be monitored during daptomycin therapy?
   a) Serum potassium
   b) CPK levels
   c) Liver enzymes
   d) INR

Answer: b) CPK levels

9. Daptomycin does NOT inhibit:
   a) DNA synthesis
   b) RNA synthesis
   c) Protein synthesis
   d) Cell wall synthesis

Answer: d) Cell wall synthesis

10. Daptomycin is classified as a:
    a) Glycopeptide
    b) Lipopeptide
    c) Macrolide
    d) Aminoglycoside

Answer: b) Lipopeptide

FAQs (minimum 5)

1. What is the primary mechanism of daptomycin?
   Calcium-dependent disruption of bacterial cell membrane potential.
2. Why is daptomycin bactericidal?
   Because membrane depolarization rapidly halts vital cellular processes.
3. Why can’t daptomycin be used in pneumonia?
   Pulmonary surfactant inactivates the drug.
4. Does daptomycin cause cell lysis?
   No, it causes cell death without lysis.
5. Why must CPK be monitored?
   Due to risk of muscle toxicity and myopathy.
6. Is daptomycin effective against Gram-negative bacteria?
   No, it is active only against Gram-positive organisms.

References

• Goodman & Gilman’s The Pharmacological Basis of Therapeutics
  https://accessmedicine.mhmedical.com
• Katzung BG. Basic and Clinical Pharmacology
  https://accessmedicine.mhmedical.com
• Tripathi KD. Essentials of Medical Pharmacology
  https://www.jaypeebrothers.com
• Harrison’s Principles of Internal Medicine
  https://accessmedicine.mhmedical.com

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