What is the mechanism by which daptomycin causes myopathy?

Mechanism of Daptomycin-Induced Myopathy

Daptomycin causes myopathy primarily through disruption of skeletal muscle cell membrane function via calcium-dependent binding, similar to its antibacterial mechanism of action against bacterial cell membranes. 1

Pathophysiological Mechanism

Daptomycin's myotoxicity involves several key processes:

1. Cell Membrane Disruption:

   • Daptomycin binds to calcium and then inserts into skeletal muscle cell membranes
   • This disrupts membrane potential and integrity, similar to how it kills bacteria 1
   • The calcium-dependent binding leads to depolarization of muscle cell membranes 2

2. Muscle Cell Damage:

   • Membrane disruption leads to increased permeability
   • This causes leakage of intracellular contents, including creatine phosphokinase (CPK)
   • Eventually leads to muscle cell death and clinical symptoms of myopathy 3

3. Dose-Dependent Effect:

   • Higher doses (≥6 mg/kg/day) are associated with greater risk of myopathy 1
   • Once-daily dosing has reduced but not eliminated the risk compared to more frequent dosing 2

Clinical Manifestations and Monitoring

Daptomycin-induced myopathy presents as:

• Muscle pain or weakness, particularly in distal extremities
• Elevated CPK levels (>10 times upper limit of normal in severe cases)
• Potential progression to rhabdomyolysis with or without acute renal failure 3

Monitoring recommendations:

• Weekly CPK monitoring is required during daptomycin therapy
• More frequent monitoring in patients with renal impairment or those on statins 3
• Early signs may include hyperkalemia, which can precede significant CPK elevations 4

Risk Factors

Several factors increase the risk of daptomycin-induced myopathy:

• Statin co-administration: Significantly increases risk of both myopathy and rhabdomyolysis 5, 6
• Obesity: Independent risk factor for progression to rhabdomyolysis 5
• Deep abscess treatment: Associated with increased myopathy risk 5
• Antihistamine co-administration: May increase myopathy risk 5

Prevention and Management

To prevent and manage daptomycin-induced myopathy:

1. Monitoring:

   • Monitor CPK weekly in all patients
   • Increase to twice-weekly monitoring when co-administering statins 5
   • Monitor for muscle pain/weakness, especially in distal extremities 3

2. Medication Management:

   • Consider temporarily discontinuing statins during daptomycin therapy 3, 5
   • Never exceed once-daily dosing of daptomycin 3
   • Use appropriate weight-based dosing

3. Discontinuation Criteria:

   • Discontinue daptomycin with unexplained muscle symptoms plus CPK >1,000 U/L
   • Discontinue if asymptomatic but CPK >2,000 U/L (≥10× ULN) 3

4. Resolution:

   • Myopathy symptoms and CPK elevations typically resolve after discontinuation of daptomycin 7

Important Clinical Considerations

• Myopathy can occur even without pronounced CPK elevation, so clinical symptoms should not be ignored 7
• Patients with renal impairment require more careful monitoring as they may be at higher risk 3
• The combination of daptomycin with statins should be avoided when possible, or managed with increased vigilance 5
• Daptomycin-induced myopathy is generally reversible upon discontinuation of the drug 2

Understanding this mechanism is crucial for early recognition and management of this potentially serious adverse effect, which can significantly impact patient morbidity and quality of life.