Towards a definition of daptomycin optimal dose: Lessons learned from experimental and clinical data

• Daptomycin bactericidal activity is predominantly concentration-dependent.
• Data showing a dose-toxicity relationship are lacking.
• The need to prevent the selection of resistant strains is a matter of concern.
• We propose new standard and high doses based on pharmacological and clinical data.

Daptomycin exhibits excellent antibacterial activity against a wide range of Gram-positive bacteria. The on-label standard daily doses for daptomycin are 4 mg/kg for skin infections and 6 mg/kg for bacteraemia or right-sided endocarditis. Daptomycin bactericidal activity is predominantly concentration-dependent and by considering the values of pharmacokinetic targets established by several authors as well as the peak and trough concentrations of daptomycin obtained at various daily dosages, it appears that these targets can easily be reached with a dose of 6 mg/kg but only for a minimum inhibitory concentration (MIC) at 0.1 mg/L, and that for increasing MICs (e.g. 0.5 mg/L or 1 mg/L) these targets may only be attained with higher dosages (i.e. ≥10 mg/kg). High-dose (HD) daptomycin therapy has also been proven to be effective for reducing the risk of selection of daptomycin-resistant strains. Given the concentration-dependent bactericidal activity of daptomycin, the absence of a dose-toxicity relationship and the need to prevent the selection of resistant strains, we propose to consider for staphylococcal (i) skin and soft-tissue infections, daily doses of daptomycin of 6 mg/kg (new standard dose) and (ii) endocarditis or bacteraemia including those associated with intravascular catheter and implant-related infections, ≥10 mg/kg (HD) when the MIC is unknown or >0.25 mg/L, and 6–10 mg/kg (intermediate doses) when the MIC is ≤0.25 mg/L. For severe and deep-seated enterococcal infections, we propose high (≥10 mg/kg) daily doses of daptomycin in combination with another active agent, especially a β-lactam.