Daptomycin

Usage

Daptomycin is a cyclic lipopeptide antibiotic indicated for the treatment of complicated skin and skin structure infections (cSSSI) caused by susceptible Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), and Staphylococcus aureus bloodstream infections (bacteremia), including right-sided infective endocarditis. It is particularly useful against vancomycin-resistant enterococci. However, it is not effective against pneumonia (including S. aureus pneumonia) as pulmonary surfactant inactivates the drug. It is also not recommended for left-sided infective endocarditis due to S. aureus. It’s pharmacological classification is antibiotic.

Daptomycin’s mechanism of action involves binding to bacterial cell membranes, causing rapid depolarization leading to inhibition of DNA, RNA, and protein synthesis, resulting in bacterial cell death.

Alternate Names

While “daptomycin” is the generic name, it is marketed under brand names such as Cubicin®, Dapzura® and Cubicin RF®.

How It Works

Pharmacodynamics: Daptomycin exerts a bactericidal effect by disrupting the bacterial cell membrane potential. This depolarization leads to the cessation of intracellular protein, DNA, and RNA synthesis, ultimately causing bacterial death. Its activity is concentration-dependent.

Pharmacokinetics:

• Absorption: Daptomycin is administered intravenously, achieving near complete bioavailability.
• Distribution: It is highly protein-bound (around 90-93%). It does not penetrate well into lung tissue.
• Metabolism: Daptomycin is not extensively metabolized.
• Elimination: Primarily eliminated renally, requiring dose adjustments in patients with renal impairment. The elimination half-life is approximately 8 hours.

Mode of Action: Daptomycin binds to the bacterial cell membrane in a calcium-dependent manner. This interaction creates transmembrane channels, leading to potassium efflux and membrane depolarization. The resultant disruption of ionic gradients inhibits protein, DNA, and RNA synthesis, culminating in cell death.

Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: Daptomycin’s primary mechanism involves direct interaction with the cell membrane rather than receptor binding, enzyme inhibition, or neurotransmitter modulation.

Dosage

Standard Dosage

Adults:

• cSSSI: 4 mg/kg intravenously once every 24 hours.
• S. aureus Bacteremia (including right-sided endocarditis): 6 mg/kg intravenously once every 24 hours.
• Higher doses (up to 12 mg/kg) may be considered for severe infections under specialist guidance and with increased monitoring of CPK levels.

Children (1-17 years):

• cSSSI: Dosage is based on age and weight, administered intravenously once daily:

  • 12-17 years: 5 mg/kg
  • 7-11 years: 7 mg/kg
  • 2-6 years: 9 mg/kg
  • 1 to <2 years: 10 mg/kg (infused over 60 minutes)

• Daptomycin is not recommended for children younger than 1 year old due to potential effects on the muscular, neuromuscular, and nervous systems.

Special Cases:

• Elderly Patients: No dosage adjustment is necessary for patients with normal renal function (CrCl ≥ 30 mL/min).
• Patients with Renal Impairment: Dosage adjustment is required. For patients with creatinine clearance (CrCl) less than 30 mL/min, including those on hemodialysis or peritoneal dialysis, administer 4 mg/kg (cSSSI) or 6 mg/kg (S. aureus bloodstream infections) every 48 hours. Hemodialysis patients can alternatively be dosed three times weekly, ideally after dialysis sessions.
• Patients with Hepatic Dysfunction: No dosage adjustment is necessary for mild to moderate hepatic impairment (Child-Pugh Class A or B). The pharmacokinetics in severe hepatic impairment have not been evaluated.
• Patients with Comorbid Conditions: Close monitoring is recommended, especially in patients with pre-existing myopathy or those receiving concomitant medications that can cause myopathy (e.g., statins).

Clinical Use Cases

Daptomycin is not recommended for pneumonia, left-sided endocarditis due to S. aureus, or other pulmonary infections as it binds to and is inactivated by pulmonary surfactant. Its use in other clinical scenarios like intubation, surgical procedures, mechanical ventilation, or ICU/emergency situations should be individualized based on infection type, severity, and patient factors. Consult with an infectious disease specialist for guidance.

Side Effects

Common Side Effects:

• Diarrhea, nausea, and vomiting
• Headache, insomnia
• Injection site reactions (pain, redness, swelling)
• Increased sweating

Rare but Serious Side Effects:

• Eosinophilic pneumonia (manifesting as fever, cough, dyspnea, and pulmonary infiltrates)
• Myopathy and rhabdomyolysis (muscle pain, weakness, elevated creatine phosphokinase [CPK])
• Peripheral neuropathy
• Allergic reactions, including anaphylaxis

Long-Term Effects:

• Clostridioides difficile-associated diarrhea (CDAD)

Adverse Drug Reactions (ADR):

• Anaphylaxis
• Angioedema
• Drug reaction with eosinophilia and systemic symptoms (DRESS)

Contraindications

• Hypersensitivity to daptomycin

Drug Interactions

• Statins (HMG-CoA reductase inhibitors): Increased risk of myopathy and rhabdomyolysis. Close monitoring of CPK levels is required. Consider temporary discontinuation of statins during daptomycin therapy.
• Drugs that prolong the QT interval: Additive effects on QT prolongation. Use with caution and monitor ECG.
• Nephrotoxic drugs: Increased risk of renal impairment. Monitor renal function closely.

Pregnancy and Breastfeeding

• Pregnancy: Daptomycin is Pregnancy Category B. Animal studies have not shown evidence of fetal harm. Limited human data suggest that it can be used in pregnancy if the potential benefit outweighs the risks, especially in the second and third trimesters.
• Breastfeeding: Daptomycin is present in breast milk in low concentrations. While the effects on nursing infants are not fully known, the risk appears to be low due to the drug’s poor oral bioavailability. Discontinuation of breastfeeding is generally recommended.

Drug Profile Summary

• Mechanism of Action: Disrupts bacterial cell membrane potential leading to cell death.
• Side Effects: Common: Diarrhea, headache, insomnia, injection site reactions. Serious: Eosinophilic pneumonia, myopathy/rhabdomyolysis, peripheral neuropathy, allergic reactions.
• Contraindications: Hypersensitivity to daptomycin.
• Drug Interactions: Statins, drugs that prolong the QT interval, nephrotoxic agents.
• Pregnancy & Breastfeeding: Pregnancy Category B; generally avoid breastfeeding.
• Dosage: cSSSI: 4mg/kg IV daily, S. aureus bacteremia: 6 mg/kg IV daily. Renal adjustments required.
• Monitoring Parameters: CPK (weekly, more frequent in renal impairment or with statin use), renal function, signs/symptoms of eosinophilic pneumonia and myopathy.

Popular Combinations

Daptomycin is often used as monotherapy. However, combination therapy may be necessary in specific cases based on infectious disease specialist recommendations.

Precautions

• General Precautions: Obtain baseline CPK and renal function tests. Monitor CPK levels at least weekly during therapy, and more frequently if at high risk for myopathy. Monitor renal function regularly. Monitor for signs/symptoms of eosinophilic pneumonia.
• Specific Populations: as detailed above.
• Lifestyle Considerations: Advise patients to avoid driving or operating machinery if experiencing side effects like dizziness or weakness.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Daptomycin?

A: For adults, the recommended dosage is 4 mg/kg IV once daily for cSSSI and 6 mg/kg IV once daily for S. aureus bacteremia (including right-sided endocarditis). Pediatric dosing is weight and age-based. Renal adjustments are required for patients with impaired renal function. Higher doses may be considered in some cases under careful monitoring.

Q2: How is Daptomycin administered?

A: Daptomycin is administered intravenously as an infusion over 30 or 60 minutes. It can also be given as a 2-minute injection in adults, but this is not recommended for children.

Q3: Can Daptomycin be used to treat pneumonia?

A: No, daptomycin is not effective against pneumonia because it is inactivated by pulmonary surfactant.

Q4: What are the most serious side effects of Daptomycin?

A: The most serious side effects include eosinophilic pneumonia, myopathy/rhabdomyolysis, peripheral neuropathy, and allergic reactions including anaphylaxis.

Q5: What are the key monitoring parameters for patients on Daptomycin?

A: Creatine phosphokinase (CPK) levels (weekly, more frequently in high-risk individuals), renal function, and monitoring for signs and symptoms of eosinophilic pneumonia and myopathy are essential.

Q6: What are the contraindications for Daptomycin use?

A: The only absolute contraindication is known hypersensitivity to daptomycin.

Q7: Can Daptomycin be used in pregnant or breastfeeding women?

A: Daptomycin is Pregnancy Category B and may be used in pregnancy if the benefit outweighs the risk. Breastfeeding is generally discouraged while receiving daptomycin, but a risk-benefit assessment should be performed.

Q8: Does Daptomycin interact with other medications?

A: Yes, clinically significant interactions can occur with statins (increased myopathy risk) and QT interval prolonging drugs. Concomitant use of nephrotoxic agents may increase the risk of renal impairment.

Q9: How does renal impairment affect Daptomycin dosage?

A: For patients with CrCl <30 mL/min, including those on hemodialysis, the dosing frequency is reduced to every 48 hours or three times per week for hemodialysis patients (after dialysis sessions).

Q10: What is the mechanism of action of Daptomycin?

A: Daptomycin binds to bacterial cell membranes, causing depolarization and ultimately leading to bacterial cell death by inhibiting protein, DNA, and RNA synthesis.