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.

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The intrapulmonary pharmacokinetics of azithromycin, clarithromycin, ciprofloxacin, and cefuroxime were studied in 68 volunteers who received single, oral doses of azithromycin (0.5 g), clarithormycin (0.5 g), ciprofloxacin (0.5 g), or cefuroxime (0.5 g). In subgroups of four subjects each, the subjects underwent bronchoscopy and bronchoalveolar lavage at timed intervals following drug administration. Drug concentrations, including those of 14-hydroxyclarithromycin (14H), were determined in serum, bronchoalveolar lavage fluid, and alveolar cells (ACs) by high-pressure liquid chromatography. Concentrations in epithelial lining fluid (ELF) were calculated by the urea diffusion method. The maximum observed concentrations (mean +/- standard deviation) of azithromycin, clarithromycin, 14H, ciprofloxacin, and cefuroxime in serum were 0.13 +/- 0.07, 1.0 +/- 0.6, 0.60 +/- 0.41, 0.95 +/- 0.32, and 1.1 +/- 0.3 microgram/ml, respectively (all at 6 h). None of the antibiotics except clarithromycin (39.6 +/- 41.1 micrograms/ml) was detectable in ELF at the 6-h bronchoscopy. The movement into and persistence in cells was different for azithromycin and clarithromycin. In ACs azithromycin was not detectable at 6 h, reached its highest concentration at 120 h, and exhibited the greatest area under the curve (7,403 micrograms.hr ml-1). The peak concentration of clarithromycin (181 +/- 94.1 micrograms/ml) was greater and occurred earlier (6 h), but the area under the curve (2,006 micrograms.hr ml-1) was less than that observed for azithromycin. 14H was detectable in ACs at 6 h (40.3 +/- 5.2 micrograms/ml) and 12 h (32.8 +/- 57.2 micrograms/ml). The peak concentration of ciprofloxacin occurred at 6 h (4.3 +/- 5.2 micrograms/ml), and the area under the curve was 35.0 micrograms.hr ml-1. The data indicate that after the administration of a single dose, azithromycin, clarithromycin, and ciprofloxacin penetrated into ACs in therapeutic concentrations and that only clarithromycin was present in ELF. The correlation of these kinetic observations with clinical efficacy or toxicity was not investigated and is unclear, but the data provide a basis for further kinetic and clinical studies.

We evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of posaconazole (POS) in a prospective, open-label study. Twenty-five healthy adults received 14 doses of POS oral suspension (400 mg twice daily) with a high-fat meal over 8 days. Pulmonary epithelial lining fluid (ELF) and alveolar cell (AC) samples were obtained via bronchoalveolar lavage, and blood samples were collected during the 24 h after the last dose. POS concentrations were determined using liquid chromatography with tandem mass spectrometry parameters. The maximum concentrations (C max ) (mean ؎ standard deviation) in plasma, ELF, and ACs were 2.08 ؎ 0.93, 1.86 ؎ 1.30, and 87.7 ؎ 65.0 g/ml. The POS concentrations in plasma, ELF, and ACs did not decrease significantly, indicating slow elimination after multiple dosing. The mean concentrations of POS in plasma, ELF, and ACs were above the MIC 90 (0.5 g/ml) for Aspergillus spp. over the 12-h dosing interval and for 24 h following the last dose. Area under the curve from 0 to 12 h (AUC 0-12 ) ratios for ELF/plasma and AC/plasma were 0.84 and 33. AUC 0-24 /MIC 90 ratios in plasma, ELF, and AC were 87.6, 73.2, and 2,860. Nine (36%) of 25 subjects had treatment-related adverse events during the course of the study, which were all mild or moderate. We conclude that a dose of 400 mg twice daily resulted in sustained plasma, ELF, and AC concentrations above the MIC 90 for Aspergillus spp. during the dosing interval. The intrapulmonary PK/PD of POS are favorable for treatment or prevention of aspergillosis, and oral POS was well tolerated in healthy adults.