title: Population pharmacokinetics of daptomycin in patients affected by severe Gram-positive infections.
abstract: A population pharmacokinetic analysis of daptomycin was performed based on therapeutic drug monitoring (TDM) data from 58 patients receiving doses of 4-12 mg/kg for the treatment of severe Gram-positive infections. At a daily dose of 8 mg/kg, daptomycin plasma concentrations (mean ± S.D.) were 76.9 ± 9.8 mg/L at the end of infusion and 52.7 ± 15.4 mg/L and 11.4 ± 5.4 mg/L at 0.5 h and 23 h after drug administration, respectively. The final model was a one-compartmental model with first-order elimination, with estimated clearance (CL) of 0.80 ± 0.14 L/h and a volume of distribution (V(d)) of 0.19 ± 0.05 L/kg. Creatinine clearance (CL(Cr)) was identified as having a significant influence on daptomycin CL, and a decrease in CL(Cr) of 30 mL/min from the median value (80 mL/min) was associated with a reduction of daptomycin CL from 0.80 L/h to 0.73 L/h. These results confirm that the presence of severe infection may be associated with an altered disposition of daptomycin, with an increased Vd. MICs were available in 41 patients and results showed that 38 and 31 subjects achieved AUC/MIC values associated with bacteriostatic (>400) and bactericidal effects (>800), respectively. Of note, 31 of these 41 subjects experienced a clinical improvement or were cured. Although daptomycin pharmacokinetics may be influenced by infections, effective AUC/MIC values were achieved in the majority of patients. The present model may be applied in clinical settings for a TDM routine on the basis of a sparse blood sampling protocol.
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, 56126 Pisa, Italy. antonello.dipaolo@med.unipi.it
authors.forename: Antonello
authors.initials: A
authors.lastname: Di Paolo
authors.forename: Carlo
authors.initials: C
authors.lastname: Tascini
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Polillo
authors.forename: Giulia
authors.initials: G
authors.lastname: Gemignani
authors.forename: Elisabet I
authors.initials: EI
authors.lastname: Nielsen
authors.forename: Guido
authors.initials: G
authors.lastname: Bocci
authors.forename: Mats O
authors.initials: MO
authors.lastname: Karlsson
authors.forename: Francesco
authors.initials: F
authors.lastname: Menichetti
authors.forename: Romano
authors.initials: R
authors.lastname: Danesi
mesh_terms: D000368:Aged; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D003404:Creatinine / Q000378:metabolism; D017576:Daptomycin / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005260:Female; D006090:Gram-Negative Bacteria / Q000187:drug effects; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008826:Microbial Sensitivity Tests
chemical_list: D000900:Anti-Bacterial Agents; D003404:Creatinine; D017576:Daptomycin
keywords: Daptomycin; Gram-positive infections; Population pharmacokinetics