Multiple-dose pharmacokinetics of daptomycin during continuous venovenous haemodiafiltration.
OBJECTIVE
Daptomycin is bactericidal against Gram-positive bacteria, with peak-dependent effect but trough-dependent toxicity. This study was performed to develop dosing recommendations in continuous venovenous haemodiaﬁltration (CVVHDF).


METHODS
Nine critically ill patients in intensive care units of the Medical University Hospital of Vienna, requiring CVVHDF due to acute renal failure and antimicrobial treatment, were included. Blood and effluent samples were collected over 72 h to determine daptomycin concentrations by HPLC. Pharmacokinetic parameters were based on 10 sampling timepoints during the first 24 h, and peak and trough samples thereafter. An open two-compartment model was fitted to each subject's plasma concentration-time data. Simulations of serum concentration-time profiles after different doses and intervals were performed using ADAPT 5.


RESULTS
Peak plasma concentrations with 6 mg/kg daptomycin were 62.2 ± 16.2, 66.1 ± 17.3 and 78.5 ± 22.1 mg/L on days 1, 2 and 3, respectively. The total clearance was 6.1 ± 4.9 mL/min, and the elimination half-life was 17.8 ± 9.7 h. Daptomycin was filtrated and could therefore be measured in the effluent. Protein binding was lower than that seen in healthy volunteers. The unbound fraction was 16 ± 4.5%. All subjects maintained trough serum concentrations above 4 mg/L, at which relevant pathogens are considered daptomycin-susceptible. Accumulation resulted when daptomycin was given every 24 h. Simulation of 8 mg/kg daptomycin given every 48 h resulted in adequate levels without accumulation.


CONCLUSIONS
We recommend 8 mg/kg daptomycin every 48 h in patients on CVVHDF and therapeutic drug monitoring, if possible.
Department of Internal Medicine I, Division of Infectious Diseases and Tropical Medicine, Center of Excellence of Medical Intensive Care (CEMIC), Medical University of Vienna, Vienna, Austria. judith.wenisch@meduniwien.ac.at
Judith M
JM
Wenisch
Brigitte
B
Meyer
Valentin
V
Fuhrmann
Katrin
K
Saria
Clara
C
Zuba
Peter
P
Dittrich
Florian
F
Thalhammer
D058186:Acute Kidney Injury / Q000150:complications / Q000628:therapy*; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001317:Austria; D001424:Bacterial Infections / Q000188:drug therapy*; D002851:Chromatography, High Pressure Liquid; D016638:Critical Illness; D017576:Daptomycin / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D005260:Female; D006094:Gram-Positive Bacteria; D006440:Hemofiltration; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D010949:Plasma / Q000737:chemistry; D013997:Time Factors
D000900:Anti-Bacterial Agents; D017576:Daptomycin