Intrapulmonary Pharmacokinetics of Linezolid

Abstract

In this study, our objective was to determine the steady-state intrapulmonary concentrations and pharmacokinetic parameters of orally administered linezolid in healthy volunteers. Linezolid (600 mg every 12 h for a total of five doses) was administered orally to 25 healthy adult male subjects. Each subgroup contained five subjects, who underwent bronchoscopy and bronchoalveolar lavage (BAL) 4, 8, 12, 24, or 48 h after administration of the last dose. Blood was obtained for drug assay prior to administration of the first dose and fifth dose and at the completion of bronchoscopy and BAL. Standardized bronchoscopy was performed without systemic sedation. The volume of epithelial lining fluid (ELF) recovered was calculated by the urea dilution method, and the total number of alveolar cells (AC) was counted in a hemocytometer after cytocentrifugation. Linezolid was measured in plasma by a high-pressure liquid chromatography (HPLC) technique and in BAL specimens and AC by a combined HPLC-mass spectrometry technique. Areas under the concentration-time curves (AUCs) for linezolid in plasma, ELF, and AC were derived by noncompartmental analysis. Half-lives for linezolid in plasma, ELF, and AC were calculated from the elimination rate constants derived from a monoexponential fit of the means of the observed concentrations at each time point. Concentrations (means ؎ standard deviations) in plasma, ELF, and AC, respectively, were 7.3 ؎ 4.9, 64.3 ؎ 33.1, and 2.2 ؎ 0.6 g/ml at the 4-h BAL time point and 7.6 ؎ 1.7, 24.3 ؎ 13.3, and 1.4 ؎ 1.3 g/ml at the 12-h BAL time point. Linezolid concentrations in plasma, ELF, and AC declined monoexponentially, with half-lives of 6.9, 7.0, and 5.7 h, respectively. For a MIC of 4, the 12-h plasma AUC/MIC and maximum concentration/MIC ratios were 34.6 and 3.9, respectively, and the percentage of time the drug remained above the MIC for the 12-h dosing interval was 100%; the corresponding ratios in ELF were 120 and 16.1, respectively, and the percentage of time the drug remained above the MIC was 100%. The long plasma and intrapulmonary linezolid half-lives and the percentage of time spent above the MIC of 100% of the dosing interval provide a pharmacokinetic rationale for drug administration every 12 h and indicate that linezolid is likely to be an effective agent for the treatment of pulmonary infections.

Colistin and anti-Gram-positive bacterial agents against Acinetobacter baumannii

“…Linezolid, which acts against a broad range of Gram-positive bacteria by preventing the formation of the 70S initiation complex 21 , is likely to be effective for treating respiratory infections 14 because of its higher concentrations in the epithelial lining fl uid (ELF) in response to a twice-daily dosing regimen. It is noteworthy that the MIC of linezolid against A. baumannii-21 fell down to the blood and ELF concentration of the drug for the recommended dose regimen (600mg twice daily) 22 .…”

“…Colistin was added at 0.125μg/ml (1/4 MIC), vancomycin at 16μg/ml, and norvancomycin at 8μg/ ml to mimic the minimal steady-state concentrations achieved with standard dosing regimens of colistin methanesulfonate (1,000,000IU colistin) 11 and continuously infused vancomycin 12 and norvacomycin 13 . Linezolid was added at 8μg/ml, a concentration that mimics the minimal steady-state plasma concentration achieved with intravenous administration of 600mg/12h 14 . Briefly, 20ml of MHBCA (Mueller-Hinton broth, cation adjusted; Becton Dickinson Microbiology Systems, Cockeysville, MD) was incubated at 37°C with the concentrations described above and an inoculum of 5×10 5 CFU of isolate 21 (A. baumannii-21).…”

Poster Abstracts

“…[16][17][18][19][20][21][22][23] The volume of ELF contained in each BALf sample was determined by the urea dilution method. Urea diffuses freely throughout the body with the concentration in plasma equal to that in other body fluids.…”

“…In our patients when we compare different level of total serum igE with response to treatment, the results do not show statistically significant. COPD patients with features of asthma have a better prognosis than the "pure emphysema" group (20). The production of IgE in allergic individuals depends on a series of interactions between B cells, T cells, mast cells and eosinophils as well as the involvement of different surface molecules and cytokines IL-4 and IL-13.…”

“…In current study, evaluation of the effect of treatment was performed after 2 weeks, because as van der Woude et al reported that, there was a significant bronchodilating and bronchoprotective effect after 2 weeks of active treatment (19). In COPD patients with elevated IgE, atopy or sputum eosinophilia, they will form a subgroup of patients with better prognosis and a greater likelihood of corticosteroid responsiveness (20). In our patients when we compare different level of total serum igE with response to treatment, the results do not show statistically significant.…”