title: Towards a definition of daptomycin optimal dose: Lessons learned from experimental and clinical data.
abstract: 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.
authors.affiliation: Infectious Diseases Department, Gustave Dron Hospital, University of Lille II, Tourcoing, France. Electronic address: esenneville@ch-tourcoing.fr.
authors.forename: Eric
authors.initials: E
authors.lastname: Senneville
authors.affiliation: Laboratory of Bacteriology, University of Nantes, Nantes, France.
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Caillon
authors.affiliation: Department of Anesthesiology, General Hospital of Béziers, Béziers, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Calvet
authors.affiliation: Laboratory of Bacteriology, University of Strasbourg, Strasbourg, France.
authors.forename: François
authors.initials: F
authors.lastname: Jehl
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D016470:Bacteremia / Q000188:drug therapy; D017576:Daptomycin / Q000008:administration & dosage*; D004697:Endocarditis, Bacterial / Q000188:drug therapy; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy; D006801:Humans; D008826:Microbial Sensitivity Tests; D017192:Skin Diseases, Bacterial / Q000188:drug therapy; D018461:Soft Tissue Infections / Q000188:drug therapy
chemical_list: D000900:Anti-Bacterial Agents; D017576:Daptomycin
keywords: Daptomycin; High-dose; Resistance; Tolerance