What are the guidelines for administering daptomycin (Cubicin) to patients at high risk of stroke, particularly those with impaired renal function?

From the Guidelines

Daptomycin should be administered with caution in patients at high risk of stroke, particularly those with impaired renal function, with a recommended dosage of 10 mg/kg/day i.v. once daily, as stated in the 2015 ESC guidelines for the management of infective endocarditis 1. When administering daptomycin to patients with impaired renal function, it is essential to monitor plasma CPK levels at least once a week, as daptomycin can cause myopathy, particularly in those with renal impairment.

• Key considerations for daptomycin administration in patients with impaired renal function include:
  • Monitoring renal function and adjusting the dose accordingly
  • Measuring CPK levels at baseline and weekly during therapy
  • Discontinuing the medication if CPK levels exceed 1,000 U/L in patients with symptoms or 2,000 U/L in asymptomatic patients
  • Maintaining adequate hydration throughout treatment to support renal function and reduce risk factors for stroke
• The 2015 ESC guidelines recommend daptomycin as an alternative therapy for infective endocarditis due to Staphylococcus spp., with a class IIa recommendation and level C evidence 1.
• It is crucial to note that daptomycin's reduced clearance in renal impairment leads to increased drug exposure, potentially exacerbating side effects that could increase stroke risk, including thrombocytopenia and potential vascular complications.
• In patients with impaired renal function, the use of daptomycin should be carefully weighed against the potential benefits and risks, and alternative therapies should be considered if necessary.

From the FDA Drug Label

The volume of distribution at steady-state (V ss) of daptomycin in healthy adult subjects was approximately 0. 1 L/kg and was independent of dose. Because renal excretion is the primary route of elimination, adjustment of daptomycin for injection dosage interval is necessary in adult patients with severe renal impairment (CL CR <30 mL/min) [see Dosage and Administration (2. 6)] . Table 12: Mean (SD) Daptomycin Population Pharmacokinetic Parameters Following Infusion of Daptomycin for Injection 4 mg/kg or 6 mg/kg to Infected Adult Patients and Noninfected Adult Subjects with Various Degrees of Renal Function Patients with Renal Impairment Population-derived pharmacokinetic parameters were determined for infected adult patients (complicated skin and skin structure infections [cSSSI] and S aureus bacteremia) and noninfected adult subjects with various degrees of renal function

Guidelines for Administering Daptomycin to Patients at High Risk of Stroke with Impaired Renal Function:

• Dosage Adjustment: Necessary in adult patients with severe renal impairment (CL CR <30 mL/min)
• Renal Excretion: Primary route of elimination
• Key Considerations:
  • Patients with mild to moderate renal impairment may not require significant dosage adjustments
  • Patients with severe renal impairment require adjustment of daptomycin for injection dosage interval
  • Monitor renal function and adjust dosage accordingly 2

From the Research

Administering Daptomycin to Patients at High Risk of Stroke

• Daptomycin is a therapeutic option for patients with underlying renal insufficiency who are vulnerable to nephrotoxicity from vancomycin 3.
• The efficacy and safety of daptomycin in patients with renal impairment have been evaluated in a multicenter retrospective analysis, which found that daptomycin demonstrated clinical and microbiologic success rates comparable with prior studies 3.
• However, discontinuation of therapy because of elevated CPK levels may have been avoided in some patients with adjustment to every 48-hour dosing for Clcr less than 30 ml/minute 3.

Daptomycin Dosage and Renal Function

• The median daptomycin dose was 6.0 mg/kg (5.8-7.8 mg/kg) administered every 24 hours in 68 patients (42.5%) and every 48 hours in 92 patients (57.5%) 3.
• A study found that significant CK elevation on daptomycin therapy was infrequently observed in a cohort of patients with severe renal dysfunction treated with daptomycin 7.5 mg/kg or greater 4.
• Higher doses and combination therapy strategies have been investigated in some difficult-to-treat infections to enhance clinical success rates and minimize the risk of resistance development 5.

Comparison with Vancomycin

• A propensity score matched analysis found that patients treated with daptomycin experienced a lower incidence of acute kidney injury (AKI) when compared to patients treated with vancomycin, with comparable efficacy 6.
• Vancomycin treatment was the only factor associated with AKI in the multivariate analysis adjusted to the propensity score 6.
• Daptomycin appears to be safer than vancomycin in terms of AKI risk in ICU patients treated for cardiovascular procedure-related infection 6.

Clinical Use and Pharmacology

• Daptomycin is a reliable agent for the treatment of Gram-positive infections, including bacteremia and endocarditis, as well as soft-tissue infections caused by Gram-positive organisms 7.
• Its role in the treatment of bone and joint infections is not well-defined, and emergence of resistance during therapy is a concern 7.
• Resistance is currently uncommon in clinical isolates, but may be prevented by use of higher doses 7.