Population pharmacokinetics at two dose levels and pharmacodynamic profiling of flucloxacillin

Landersdorfer, C. B., Kirkpatrick, C. M. J., Kinzig-Schippers, M., Bulitta, J. B., Holzgrabe, U., Drusano, G. L. and Sörgel, F. (2007) Population pharmacokinetics at two dose levels and pharmacodynamic profiling of flucloxacillin. Antimicrobial Agents and Chemotherapy, 51 9: 3290-3297. doi:10.1128/AAC.01410-06

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Author Landersdorfer, C. B.
Kirkpatrick, C. M. J.
Kinzig-Schippers, M.
Bulitta, J. B.
Holzgrabe, U.
Drusano, G. L.
Sörgel, F.
Title Population pharmacokinetics at two dose levels and pharmacodynamic profiling of flucloxacillin
Journal name Antimicrobial Agents and Chemotherapy   Check publisher's open access policy
ISSN 0066-4804
Publication date 2007
Sub-type Article (original research)
DOI 10.1128/AAC.01410-06
Open Access Status File (Publisher version)
Volume 51
Issue 9
Start page 3290
End page 3297
Total pages 8
Place of publication Washington, DC, United States
Publisher Amer Soc Microbiology
Collection year 2008
Language eng
Subject C1
320503 Clinical Pharmacology and Therapeutics
730101 Infectious diseases
Abstract Flucloxacillin is often used for the treatment of serious infections due to sensitive staphylococci. The pharmacokinetic (PK)-pharmacodynamic (PD) breakpoint of flucloxacillin has not been determined by the use of population PK. Targets based on the duration of non-protein-bound concentrations above the MIC (fT(> MIC)) best correlate with clinical cure rates for beta-lactams. We compared the breakpoints for flucloxacillin between several dosage regimens. In a randomized, two-way crossover study, 10 healthy volunteers received 500 mg and 1,000 mg flucloxacillin as 5-min intravenous infusions. Drug concentrations were determined by high-pressure liquid chromatography. We used the programs WinNonlin for noncompartmental analysis and statistics and NONMEM for population PK and Monte Carlo simulation. We compared the probability of target attainment (PTA) for intermittent- and continuous-dosage regimens based on the targets of fT(> MIS)s of >= 50% and >= 30% of the dosing interval. The clearance and the volume of distribution were very similar after the administration of 500 mg and 1,000 mg flucloxacillin. We estimated renal and nonrenal clearances of 5.37 liters/h (coefficient of variation, 19%) and 2.73 liters/h (33%). For near maximal killing (target, fT(> MIC) of >= 50%) flucloxacillin showed a robust (>= 90%) PTA up to MICs of 0.75 to 1 mg/liter (PTA of 860/v at 1 mg/liter) for a continuous or a prolonged infusion of 6 g/day. Short-term infusions of 6 g/day had a lower breakpoint of 0.25 to 0.375 mg/liter. The flucloxacillin PK was linear for doses of 500 mg and 1,000 mg. Prolonged and continuous infusion at a 66% lower daily dose achieved the same PK-PD breakpoints as short-term infusions. Prolonged infusion and continuous infusion are appealing options for the treatment of serious infections caused by sensitive staphylococci.
Keyword Microbiology
Pharmacology & Pharmacy
Continuous-infusion Flucloxacillin
Monte-carlo-simulation
Healthy-subjects
Antibiotics
Resistance
Selection
Efficacy
Therapy
Drug
Mice
Q-Index Code C1
Q-Index Status Confirmed Code

 
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Created: Mon, 18 Feb 2008, 14:56:07 EST