Intrapulmonary pharmacodynamics of high-dose levofloxacin in subjects with chronic bronchitis or chronic obstructive pulmonary disease

摘要

The objective of this study was to determine the plasma and intrapulmonary pharmacokinetic parameters of intravenously administered levofloxacin in subjects with stable chronic lung disease. Three doses of 1000mg levofloxacin were administered once daily to 16 adult subjects divided into four groups of 4 subjects each. Standardised bronchoscopy and timed bronchoalveolar lavage (BAL) were performed at 4 h, 8 h, 12 h and 24 h following administration of the last dose. Blood was obtained for drug assay prior to drug administration, at the end of the last infusion (maximum concentration (C-max)) and at the time of BAL. Levofloxacin was measured using a high-performance liquid chromatographic tandem mass spectrometric (HPLC/MS/MS) technique. Plasma, epithelial lining fluid (ELF) and alveolar cell (AC) pharmacokinetics were derived using non-compartmental methods. C-max/MIC90 and area under the concentration-time curve for 0-24 h after the last dose (AUC(0-24 h))/MIC90 ratios were calculated for respiratory pathogens with minimum inhibitory concentrations for 90% of the organisms (MIC90) of 0.03-2 Vg/mL. The C-max (mean standard deviation), AUC(0-24 h) and half-life were, respectively, 9.2 +/- 2.7 Vg/mL, 130 mu g h/mL and 8.7 It for plasma, 22.8 +/- 12.9 mu g/mL, 260 mu g h/mL and 7.0 h for ELF and 76.3 +/- 28.7 mu g/mL, 1492 mu g h/mL and 49.5 h for ACs. Levofloxacin concentrations were quantitatively greater in ACs than in ELF or plasma at all time points, however only the differences between AC concentration and ELF or plasma concentrations in the 4-h and 8-h time groups were statistically significant. C-max/MIC90 and AUC/MIC90 ratios in ELF were, respectively, 11.4 and 130 for Mycoplasma pneumoniae, 22.8 and 260 for Streptococcus pneumoniae, 91.2 and 1040 for Chlamydia pneumoniae and 760 and 8667 for Haernophilus influenzae. In ACs the ratios were 3 8.2 and 746 for M. pneumoniae, 76.3 and 1492 for S. pneumoniae, 305 and 5968 for C. pneumoniae and 2543 and 49 733 for H. influenzae. In conclusion, C-max/MIC90 and AUC/MIC90 ratios provide a pharmacokinetic rationale for once-daily administration of a 1000 mg dose of levofloxacin and are favourable for the treatment of respiratory infection in patients with chronic lung disease. (C) 2007 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.