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1.
OBJECTIVES: The steady-state concentrations of clarithromycin in plasma were compared with concomitant concentrations in epithelial lining fluid (ELF) and alveolar macrophages (AM) obtained from intrapulmonary samples during bronchoscopy and bronchoalveolar lavage (BAL). Concentrations of the major metabolite, 14-hydroxyclarithromycin, were also determined in plasma and AM. MATERIALS AND METHODS: Forty-two healthy, non-smoking adult subjects (age: 18-54 years; 19 females, 23 males) received oral clarithromycin extended-release formulation (1000 mg once daily for five consecutive days). Bronchoscopy and BAL were carried out once in each subject at either 3, 6, 9, 12, 24 or 48 h after the last administered dose of clarithromycin. In addition, three subjects who did not take clarithromycin served as controls and underwent bronchoscopy at 0 h. Drug concentrations in plasma, ELF, and AM were determined by high-performance liquid chromatography. RESULTS: Clarithromycin was extensively concentrated in ELF [range of mean (+/-s.d.) concentrations: 6.38 +/- 3.92 to 11.50 +/- 6.65 mg/L] and AM (127.0 +/- 61.5 to 573.8 +/- 309.3 mg/L) than simultaneous plasma concentration (0.75 +/- 0.31 to 2.22 +/- 0.72 mg/L). The ranges of mean (+/-s.d.) concentrations of 14-hydroxyclarithromycin in plasma and AM were 0.52 +/- 0.29 to 0.80 +/- 0.31 mg/L and 22.1 +/- 13.5 to 49.5 +/- 16.2 mg/L, respectively. CONCLUSIONS: Once-daily dosing of extended-release formulation clarithromycin 1000 mg produced significantly (P < 0.05) higher steady-state concentrations of clarithromycin in ELF (2-14 times) and AM (50-700 times) compared to simultaneous plasma concentrations throughout the 24 h period after drug administration. The 14-hydroxy metabolite of clarithromycin achieved significantly (P < 0.05) higher steady-state concentrations in AM (18-180 times) compared with concurrent plasma concentrations.  相似文献   

2.
The steady-state concentrations of solithromycin in plasma were compared with concomitant concentrations in epithelial lining fluid (ELF) and alveolar macrophages (AM) obtained from intrapulmonary samples during bronchoscopy and bronchoalveolar lavage (BAL) in 30 healthy adult subjects. Subjects received oral solithromycin at 400 mg once daily for five consecutive days. Bronchoscopy and BAL were carried out once in each subject at either 3, 6, 9, 12, or 24 h after the last administered dose of solithromycin. Drug concentrations in plasma, ELF, and AM were assayed by a high-performance liquid chromatography-tandem mass spectrometry method. Solithromycin was concentrated extensively in ELF (range of mean [± standard deviation] concentrations, 1.02 ± 0.83 to 7.58 ± 6.69 mg/liter) and AM (25.9 ± 20.3 to 101.7 ± 52.6 mg/liter) in comparison with simultaneous plasma concentrations (0.086 ± 0.070 to 0.730 ± 0.692 mg/liter). The values for the area under the concentration-time curve from 0 to 24 h (AUC(0-24) values) based on mean and median ELF concentrations were 80.3 and 63.2 mg · h/liter, respectively. The ratio of ELF to plasma concentrations based on the mean and median AUC(0-24) values were 10.3 and 10.0, respectively. The AUC(0-24) values based on mean and median concentrations in AM were 1,498 and 1,282 mg · h/L, respectively. The ratio of AM to plasma concentrations based on the mean and median AUC(0-24) values were 193 and 202, respectively. Once-daily oral dosing of solithromycin at 400 mg produced steady-state concentrations that were significantly (P < 0.05) higher in ELF (2.4 to 28.6 times) and AM (44 to 515 times) than simultaneous plasma concentrations throughout the 24-h period after 5 days of solithromycin administration.  相似文献   

3.
This study assessed the pulmonary disposition of tedizolid, an oxazolidinone, in adult volunteers receiving 200 mg of the prodrug tedizolid phosphate orally every 24 h for 3 days to steady state. Plasma samples were collected over the dosing interval, and participants were randomized to undergo bronchoalveolar lavage (BAL) at 2, 6, 12, or 24 h after the last dose. Drug concentrations in plasma, BAL fluid, and alveolar macrophages (AM) were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the urea correction method was used to calculate epithelial lining fluid (ELF) concentrations. Pharmacokinetic parameters were estimated by noncompartmental methods followed by compartmental population pharmacokinetics. Penetration was calculated as the area under the concentration-time curve during the dosing interval (AUC(0-24)) for ELF and AM relative to the free AUC(0-24) (fAUC(0-24)) in plasma. The half-life and volume of distribution in plasma were 9.23 ± 2.04 h and 108.25 ± 20.53 liters (means ± standard deviations), respectively. Total AUC(0-24) in plasma was 25.13 ± 5.78 μg · h/ml. Protein binding was 89.44% ± 1.58%, resulting in a mean fAUC(0-24) of 2.65 ± 0.72 μg · h/ml in plasma. Mean concentrations (μg/ml) at 2, 6, 12, and 24 h were 9.05 ± 3.83, 4.45 ± 2.18, 5.62 ± 1.99, and 1.33 ± 0.59 in ELF and 3.67 ± 1.02, 4.38 ± 2.18, 1.42 ± 0.63, and 1.04 ± 0.52 in AM. ELF and AM penetration ratios were 41.2 and 20.0. The mean ELF penetration ratio after population analyses was 39.7. This study demonstrates that tedizolid penetrates into ELF and AM to levels approximately 40-fold and 20-fold, respectively, higher than free-drug exposures in plasma.  相似文献   

4.
The bronchopulmonary and plasma pharmacokinetics of clarithromycin (CLA; 500 mg given twice daily for nine doses) or azithromycin (AZ; 500 mg for the first dose and then 250 mg once daily for four doses) were assessed in 41 healthy nonsmokers. Bronchoalveolar lavage was performed at 4, 8, 12, or 24 h after administration of the last dose. The concentrations (mean +/- standard deviation) of CLA, 14-hydroxyclarithromycin, and AZ were measured in plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) cells by high-performance liquid chromatography assay. The concentrations of CLA achieved in ELF were 34.02 +/- 5.16 micrograms/ml at 4 h, 20.63 +/- 4.49 micrograms/ml at 8 h, 23.01 +/- 11.9 micrograms/ml at 12 h, and 4.17 +/- 0.29 microgram/ml at 24 h, whereas at the same time points AZ concentrations remained below the limit of assay sensitivity (0.01 microgram/ml) for all but two subjects. The concentrations of CLA in the AM cells were significantly higher than those of AZ at 8 h (703 +/- 235 and 388 +/- 53 micrograms/ml, respectively). However, the ratio of the concentration in AM cells/concentration in plasma was significantly higher for AZ than for CLA for all time points because of the lower concentration of AZ in plasma. These results indicate that while AZ has higher tissue concentration to plasma ratios, as shown by other investigators, the absolute concentrations of CLA in AM cells and ELF are higher for up to 8 and 12 h, respectively, after administration of the last dose.  相似文献   

5.
Steady-state concentrations of telavancin, a novel, bactericidal lipoglycopeptide, were determined in the plasma, pulmonary epithelial lining fluid (ELF), and alveolar macrophages (AMs) of 20 healthy subjects. Telavancin at 10 mg of drug/kg of body weight/day was administered as a 1-h intravenous infusion on three successive days, with bronchoalveolar lavage performed on five subjects, each at 4, 8, 12, and 24 h after the last dose. Plasma samples were collected before the first and third infusions and at 1, 2, 3, 4, 8, 12, and 24 h after the third infusion. The plasma telavancin concentration-time profile was as reported previously. Telavancin (mean +/- standard deviation) penetrated well into ELF (3.73 +/- 1.28 microg/ml at 8 h and 0.89 +/- 1.03 microg/ml at 24 h) and extensively into AMs (19.0 +/- 16.8 microg/ml at 8 h, 45.0 +/- 22.4 microg/ml at 12 h, and 42.0 +/- 31.4 microg/ml at 24 h). Mean concentrations in AMs and plasma at 12 h were 45.0 microg/ml and 22.9 microg/ml (mean AM/plasma ratio, 1.93), respectively, and at 24 h were 42.0 microg/ml and 7.28 microg/ml (mean AM/plasma ratio, 6.67), respectively. Over the entire dosing interval, telavancin was present in ELF and AMs at concentrations up to 8-fold and 85-fold, respectively, above its MIC 90 for methicillin-resistant Staphylococcus aureus (0.5 microg/ml). Pulmonary surfactant did not affect telavancin's in vitro antibacterial activity. Telavancin was well tolerated. These results support the proposal for further clinical evaluation of telavancin for treating gram-positive respiratory infections.  相似文献   

6.
The purpose of this study was to compare the concentrations of levofloxacin and azithromycin in steady-state plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) after intravenous administration. Thirty-six healthy, nonsmoking adult subjects were randomized to either intravenous levofloxacin (500 or 750 mg) or azithromycin (500 mg) once daily for five doses. Venipuncture and bronchoscopy with bronchoalveolar lavage were performed in each subject at either 4, 12, or 24 h after the start of the last antibiotic infusion. The mean concentrations of levofloxacin and azithromycin in plasma were similar to those previously published. The dosing regimens of levofloxacin achieved significantly (P < 0.05) higher concentrations in steady-state plasma than azithromycin during the 24 h after drug administration. The respective mean (+/- standard deviation) concentrations at 4, 12, and 24 h in ELF for 500 mg of levofloxacin were 11.01 +/- 4.52, 2.50 +/- 0.97, and 1.24 +/- 0.55 micro g/ml; those for 750 mg of levofloxacin were 12.94 +/- 1.21, 6.04 +/- 0.39, and 1.73 +/- 0.78 micro g/ml; and those for azithromycin were 1.70 +/- 0.74, 1.27 +/- 0.47, and 2.86 +/- 1.75 micro g/ml. The differences in concentrations in ELF among the two levofloxacin groups and azithromycin were significantly (P < 0.05) higher at the 4- and 12-h sampling times. The respective concentrations in AM for 500 mg of levofloxacin were 83.9 +/- 53.2, 18.3 +/- 6.7, and 5.6 +/- 3.2 micro g/ml; those for 750 mg of levofloxacin were 81.7 +/- 37.0, 78.2 +/- 55.4, and 13.3 +/- 6.5 micro g/ml; and those for azithromycin were 650 +/- 259, 669 +/- 311, and 734 +/- 770 micro g/ml. Azithromycin achieved significantly (P < 0.05) higher concentrations in AM than levofloxacin at all sampling times. The concentrations in ELF and AM following intravenous administration of levofloxacin and azithromycin were higher than concentrations in plasma. Further studies are needed to determine the clinical significance of such high intrapulmonary concentrations in patients with respiratory tract infections.  相似文献   

7.
Lung concentrations of telithromycin after oral dosing   总被引:6,自引:0,他引:6  
Concentrations of telithromycin were measured in plasma, bronchial mucosa (BM), epithelial lining fluid (ELF) and alveolar macrophages (AM) following multiple oral doses. Concentrations were determined using a microbiological assay. There were 20 subjects in the study, allocated to three nominal time periods: 2, 12 and 24 h. Mean concentrations in plasma, BM, ELF and AM for 2, 12 and 24 h were as follows: 2 h, 1.86 mg/L, 3.88 mg/kg, 14.89 mg/L and 69.32 mg/L; 12 h, 0.23 mg/L, 1.41 mg/kg, 3.27 mg/L and 318.1 mg/L; and 24 h, 0.08 mg/L, 0.78 mg/kg, 0.97 mg/L and 161.57 mg/L. These concentrations of telithromycin in BM and ELF exceeded for 24 h the mean MIC90s of the common respiratory pathogens Streptococcus pneumoniae (0.12 mg/L) and Moraxella catarrhalis (0.03 mg/L), as well as the atypical microorganism Mycoplasma pneumoniae (0.001 mg/L), and suggest that telithromycin may be effective for the treatment of community-acquired pneumonia and chronic obstructive pulmonary disease.  相似文献   

8.
The steady-state concentrations of clarithromycin and azithromycin in plasma were compared with concomitant concentrations in epithelial lining fluid (ELF) and alveolar macrophages (AM) obtained in intrapulmonary samples during bronchoscopy and bronchoalveolar lavage from 40 healthy, nonsmoking adult volunteers. Mean plasma clarithromycin, 14-(R)-hydroxyclarithromycin, and azithromycin concentrations were similar to those previously reported. Clarithromycin was extensively concentrated in ELF (range of mean +/- standard deviation concentrations, 34.4 +/- 29.3 microg/ml at 4 h to 4.6 +/- 3.7 microg/ml at 24 h) and AM (480 +/- 533 microg/ml at 4 h to 99 +/- 50 microg/ml at 24 h). The concentrations of azithromycin in ELF were 1.01 +/- 0.45 microg/ml at 4 h to 1.22 +/- 0.59 microg/ml at 24 h, and those in AM were 42.7 +/- 28.7 microg/ml at 4 h to 41.7 +/- 12.1 microg/ml at 24 h. The concentrations of 14-(R)-hydroxyclarithromycin in the AM ranged from 89.3 +/- 52.8 microg/ml at 4 h to 31.3 +/- 17.7 microg/ml at 24 h. During the period of 24 h after drug administration, azithromycin and clarithromycin achieved mean concentrations in ELF and AM higher than the concomitant concentrations in plasma.  相似文献   

9.
This study evaluated the pulmonary disposition of eravacycline in 20 healthy adult volunteers receiving 1.0 mg of eravacycline/kg intravenously every 12 h for a total of seven doses over 4 days. Plasma samples were collected at 0, 1, 2, 4, 6, and 12 h on day 4, with each subject randomized to undergo a single bronchoalveolar lavage (BAL) at 2, 4, 6, or 12 h. Drug concentrations in plasma, BAL fluid, and alveolar macrophages (AM) were determined by liquid chromatography-tandem mass spectrometry, and the urea correction method was used to calculate epithelial lining fluid (ELF) concentrations. Pharmacokinetic parameters were estimated by noncompartmental methods. Penetration for ELF and AM was calculated by using a ratio of the area under the concentration time curve (AUC0–12) for each respective parameter against free drug AUC (fAUC0–12) in plasma. The total AUC0–12 in plasma was 4.56 ± 0.94 μg·h/ml with a mean fAUC0–12 of 0.77 ± 0.14 μg·h/ml. The eravacycline concentrations in ELF and AM at 2, 4, 6, and 12 h were means ± the standard deviations (μg/ml) of 0.70 ± 0.30, 0.57 ± 0.20, 0.34 ± 0.16, and 0.25 ± 0.13 with a penetration ratio of 6.44 and 8.25 ± 4.55, 5.15 ± 1.25, 1.77 ± 0.64, and 1.42 ± 1.45 with a penetration ratio of 51.63, respectively. The eravacycline concentrations in the ELF and AM achieved greater levels than plasma by 6- and 50-fold, respectively, supporting further study of eravacycline for patients with respiratory infections.  相似文献   

10.
We studied the penetration of dapsone into the epithelial lining fluid (ELF) of sixteen human immunodeficiency virus type 1-infected patients who had received the drug at a dose of 100 mg twice weekly as primary prophylaxis for Pneumocystis carinii pneumonia. Bronchoscopy, bronchoalveolar lavage (BAL), and venipuncture were performed for each patient at a specific time after administration of the last dose of dapsone. Dapsone concentrations in plasma and BAL were determined by high-performance liquid chromatography. The apparent volume of ELF recovered by BAL was determined by using urea as an endogenous marker. The mean concentrations of dapsone in ELF at 2 h (five patients), 4 h (three patients), 12 h (two patients), 24 h (three patients), and 48 h (three patients) were 0.95, 0.70, 1.55, 0.23, and 0.45 mg/liter, respectively, while concentrations in plasma were 1.23, 0.79, 1.31, 0.83, and 0.18 mg/liter, respectively. Dapsone concentrations in ELF were 76, 79, 115, 65, and 291% of those observed in plasma at the same times, respectively. These data show that dapsone is well distributed into ELF and that a twice-weekly 100-mg prophylactic regimen results in sustained concentrations in this compartment.  相似文献   

11.
OBJECTIVES: A validated microbiological assay was used to measure concentrations of iclaprim (AR-100) in plasma, bronchial mucosa (BM), alveolar macrophages (AM) and epithelial lining fluid (ELF) after a single 1.6 mg/kg intravenous 60 min iv infusion of iclaprim. METHODS: Male volunteers were randomly allocated to three nominal sampling time intervals 1-2 h (Group A), 3-4 h (Group B) and 5.5-7.0 h (Group C) after the start of the drug infusion. RESULTS: Mean iclaprim concentrations in plasma, BM, AM and ELF, respectively, were for Group A 0.59 mg/L (SD 0.18), 0.51 mg/kg (SD 0.17), 24.51 mg/L (SD 21.22) and 12.61 mg/L (SD 7.33); Group B 0.24 mg/L (SD 0.05), 0.35 mg/kg (SD 0.17), 7.16 mg/L (SD 1.91) and 6.38 mg/L (SD 5.17); and Group C 0.14 mg/L (SD 0.05), no detectable level in BM, 5.28 mg/L (SD 2.30) and 2.66 mg/L (SD 2.08). CONCLUSIONS: Iclaprim concentrations in ELF and AM exceeded the MIC(90) for penicillin-susceptible Streptococcus pneumoniae (MIC90 0.06 mg/L), penicillin-intermediate S. pneumoniae (MIC90 2 mg/L), penicillin-resistant S. pneumoniae (MIC90 4 mg/L) for 7, 7 and 4 h, respectively, and Chlamydia pneumoniae (MIC90 0.5 mg/L) for 7 h. Mean iclaprim concentrations in ELF exceeded the MIC90 for Haemophilus influenzae (MIC90 4 mg/L) and Moraxella catarrhalis (MIC90 8 mg/L) for up to 4 and 2 h, respectively; in AM the MIC90 was exceeded for up to 7 h. Furthermore, the MIC90 for methicillin-resistant Staphylococcus aureus of 0.12 mg/L was exceeded at all sites for up to 7 h. These data suggest that iclaprim reaches lung concentrations that should be effective in the treatment of community-acquired pneumonia.  相似文献   

12.
The objective of the present study was to evaluate the effects of gender, AIDS, and acetylator status on the steady-state concentrations of orally administered isoniazid in plasma and lungs. Isoniazid was administered at 300 mg once daily for 5 days to 80 adult volunteers. Subjects were assigned to eight blocks according to gender, presence or absence of AIDS, and acetylator status. Blood was obtained prior to administration of the first dose, 1 h after administration of the last dose, and at the completion of bronchoscopy and bronchoalveolar lavage (BAL), which was performed 4 h after administration of the last dose. The metabolism of caffeine was used to determine acetylator status. Standardized bronchoscopy was performed without systemic sedation. The volume of epithelial lining fluid (ELF) recovered was calculated by the urea dilution method. Isoniazid concentrations in plasma, BAL fluid, and alveolar cells (ACs) were measured by high-performance liquid chromatography. AIDS status or gender had no significant effect on the concentrations of isoniazid in plasma at 1 or 4 h. Concentrations in plasma at 4 h and concentrations in ELF were greater in slow acetylators than fast acetylators. The concentration in plasma (1.85 +/- 1.60 microg/ml [mean +/- standard deviation; n = 80]) at 1 h following administration of the last dose was not significantly different from that in ELF (2.25 +/- 3.50 microg/ml) or ACs (2.61 +/- 5.01 microg/ml). For the entire study group, concentrations in plasma at 1 h were less than 1.0, 2.0, and 3.0 microg/ml for 34.7, 60, and 82.7% of the subjects, respectively; concentrations in ELF were less than 1.0, 2.0, and 3.0 microg/ml in 30 (37.5%), 53 (66.0%), and 58 (72.5%) of the subjects, respectively; and concentrations in ACs were less than 1.0, 2.0, and 3.0 microg/ml in 43 (53.8%), 59 (73.8%), and 65 (81.3%) of the subjects, respectively. The concentrations of orally administered isoniazid in plasma were not affected by gender or the presence of AIDS. The concentrations in plasma at 4 h and the concentrations in ELF, but not the concentrations in ACs, were significantly greater in slow acetylators than fast acetylators. Concentrations in plasma and lungs were low compared to recommended therapeutic concentrations in plasma and published MICs of isoniazid for Mycobacterium tuberculosis. The optimal concentrations of isoniazid in ACs and ELF are unknown, but these data suggest that the drug enters these compartments by passive diffusion and achieves concentrations similar to those found in plasma.  相似文献   

13.
The concentrations of moxifloxacin achieved after a single 400 mg dose were measured in serum, epithelial lining fluid (ELF), alveolar macrophages (AM) and bronchial mucosa (BM). Concentrations were determined using a microbiological assay. Nineteen patients undergoing fibre-optic bronchoscopy were studied. Mean serum, ELF, AM and BM concentrations at 2.2, 12 and 24 h were as follows: 2.2 h: 3.2 mg/L, 20.7 mg/L, 56.7 mg/L, 5.4 mg/kg; 12 h: 1.1 mg/L, 5.9 mg/L, 54.1 mg/L, 2.0 mg/kg; 24 h: 0.5 mg/L, 3.6 mg/L, 35.9 mg/L, 1.1 mg/kg, respectively. These concentrations exceed the MIC(90)s for common respiratory pathogens such as Streptococcus pneumoniae (0.25 mg/L), Haemophilus influenzae (0.03 mg/L), Moraxella catarrhalis (0.12 mg/L), Chlamydia pneumoniae (0.12 mg/L) and Mycoplasma pneumoniae (0. 12 mg/L) and indicate that moxifloxacin should be effective in the treatment of community-acquired, lower respiratory tract infections.  相似文献   

14.
Telithromycin (HMR 3647) is the first member of a new family of antimicrobials, the ketolides, developed specifically for the treatment of community-acquired respiratory tract infections. Telithromycin has proven in vitro activity against both common and atypical respiratory tract pathogens. The penetration of telithromycin into bronchopulmonary tissues and subsequent elimination from these sites were evaluated in four groups (groups A, B, C, and D) of six healthy male subjects who received telithromycin at 800 mg once daily for 5 days. Subjects in groups A, B, C, and D underwent fiberoptic bronchoscopy and bronchoalveolar lavage 2, 8, 24, and 48 h after receipt of the last dose, respectively. The concentration of telithromycin in the alveolar macrophages, epithelial lining fluid (ELF), and plasma was determined by the agar diffusion method with Bacillus subtilis ATCC 6633 as the test organism. The concentration of telithromycin in alveolar macrophages markedly exceeded that in plasma, reaching up to 146 times the concentration in plasma 8 h after dosing (median concentration, 81 mg/liter). Telithromycin was retained in alveolar macrophages 24 h after dosing (median concentration, 23 mg/liter), and it was still quantifiable 48 h after dosing (median concentration, 2.15 mg/liter). Telithromycin median concentrations in ELF also markedly exceeded concentrations in plasma (median concentration in ELF, 3.7 mg/liter 8 h after dosing). Telithromycin achieves high and sustained concentrations in ELF and in alveolar macrophages, while it maintains adequate levels in plasma, providing an ideal pharmacokinetic profile for effective treatment of community-acquired respiratory tract infections caused by either common or atypical, including intracellular, respiratory tract pathogens.  相似文献   

15.
A microbiological assay was used to measure concentrations of garenoxacin (BMS-284756) in plasma, bronchial mucosa (BM), alveolar macrophages (AM) and epithelial lining fluid (ELF), following a single 600 mg oral dose. Twenty-four healthy subjects were allocated into four nominal time intervals after the dose, 2.5-3.5, 4.5-5.5, 10.5-11.5 and 23.5-24.5 h. Mean concentrations in plasma, BM, AM and ELF, respectively, for the four nominal time windows were for 2.5-3.5 h 10.0 mg/L (S.D. 2.8), 7.0 mg/kg (S.D. 1.3), 106.1 mg/L (S.D. 60.3) and 9.2 mg/L (S.D. 3.6); 4.5-5.5 h 8.7 mg/L (S.D. 2.2), 6.0 mg/kg (S.D. 1.9), 158.6 mg/L (S.D. 137.4) and 14.3 mg/L (S.D. 8.2); 10.5-11.5 h 6.1 mg/L (S.D. 1.9), 4.0 mg/kg (S.D. 1.4), 76.0 mg/L (S.D. 47.7) and 7.9 mg/L (S.D. 4.6); and 23.5-24.5 h 2.1 mg/L (S.D. 0.5), 1.7 mg/kg (S.D. 0.7), 30.7 mg/L (S.D. 12.9) and 3.3 mg/L (S.D. 2.3). Concentrations at all sites exceeded MIC(90)s for the common respiratory pathogens Haemophilus influenzae (0.03 mg/L), Moraxella catarrhalis (0.015 mg/L) and Streptococcus pneumoniae (0.06 mg/L). These data suggest that garenoxacin should be effective in the treatment of community-acquired pneumonia and chronic obstructive pulmonary disease.  相似文献   

16.
A single inhaled dose of laninamivir octanoate (LO), a long-acting neuraminidase inhibitor, exhibits efficacy in treating both adult and pediatric patients with influenza virus infection. The intrapulmonary pharmacokinetics (PK) of LO and laninamivir, a pharmacologically active metabolite, were investigated by a single-center, open-label study of healthy adult volunteers. Subgroups of five subjects each underwent bronchoalveolar lavage (BAL) 4, 8, 24, 48, 72, 168, and 240 h following a single inhaled administration of LO (40 mg). Plasma, BAL fluid, and alveolar macrophages (AM) were analyzed to determine LO and laninamivir concentrations, using validated liquid chromatography-tandem mass spectrometry methods. The concentrations in epithelial lining fluid (ELF) and AM from the first and subsequent BAL fluid samples were determined separately to explore the drug distribution in airways. Mean laninamivir concentrations in ELF, calculated using the first BAL fluids and BAL fluids collected 4 h after inhaled administration, were 8.57 and 2.40 μg/ml, respectively. The laninamivir concentration in ELF decreased with a longer half-life than that in plasma, and it exceeded the 50% inhibitory concentrations for viral neuraminidases at all time points examined for 240 h after the inhalation. Laninamivir exposure in ELF from the first BAL samples was 3.2 times higher than that in ELF from the subsequent BAL fluid samples. ELF concentration profiles of laninamivir support its long-lasting effect for treatment of patients with influenza virus infection by a single inhaled administration.  相似文献   

17.
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 (Cmax) (mean ± standard deviation) in plasma, ELF, and ACs were 2.08 ± 0.93, 1.86 ± 1.30, and 87.7 ± 65.0 μg/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 MIC90 (0.5 μg/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 (AUC0-12) ratios for ELF/plasma and AC/plasma were 0.84 and 33. AUC0-24/MIC90 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 MIC90 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.  相似文献   

18.
BACKGROUND: Bronchoalveolar lavage (BAL) is an established technique for measuring antibiotic concentrations in the epithelial lining fluid (ELF) of the bronchiolar and alveolar regions; however, the results may not reflect concentrations in bronchial regions. Bronchoscopic microsampling (BMS) is a technique that makes it possible to obtain multiple samples from bronchial ELF. OBJECTIVE: BMS and BAL were used to analyze the pharmacokinetics of gatifloxacin in bronchial ELF from healthy young adult subjects and adult patients with chronic bronchitis. METHODS: Bronchial ELF samples were obtained by BMS at 1, 2, 3, 4, 6, 10, and 24 hours after administration of a single oral dose of gatifloxacin 200 mg in healthy young adult (aged 20-25 years) subjects, and at 1, 2, 4, and 10 hours after a single dose in patients with chronic bronchitis (aged > or =20 years). At least 1 month after the initial BMS, alveolar (BAL) and bronchial (BMS) ELF samples were obtained from another group of healthy subjects 2 hours after administration of a single oral dose of gatifloxacin 200 mg for comparison of gatifloxacin concentrations in samples obtained by the 2 techniques. RESULTS: Bronchial ELF samples were obtained from 8 healthy subjects and 5 patients with chronic bronchitis; alveolar ELF samples were obtained from a separate group of 5 healthy subjects. For the healthy subjects, the mean (SD) AUC(0-24) in serum and bronchial ELF, corrected for mg/kg doses, was 4.6 (1.1) and 7.6 (3.5) mg x h/L, respectively. In the patients with chronic bronchitis, the AUC(0-10) in serum and bronchial ELF, corrected for mg/kg doses, was 3.9 (0.8) and 4.1 (1.5) mg x h/L. The C(max) in serum and bronchial ELF, corrected for mg/kg doses, was 0.6 (0.2) and 1.4 (0.8) mg/L in healthy subjects and 0.7 (0.2) and 0.7 (0.2) mg/L in patients with chronic bronchitis. In healthy subjects, the C(max) and AUC(0-24) were significantly higher in bronchial ELF than in serum (both, P < 0.05). Gatifloxacin concentrations were significantly lower in bronchial ELF obtained by BMS than in alveolar ELF obtained by BAL (P < 0.05). CONCLUSIONS: Based on the findings of this study in small numbers of healthy young adult volunteers and patients with chronic bronchitis, BMS appears to be a promising method for measuring drug concentrations and determining the pharmacokinetic profile of gatifloxacin in bronchial ELF. Additional studies are needed to correlate measured concentrations obtained by BMS with clinical and/or microbiologic outcomes in larger populations.  相似文献   

19.
In order to illustrate the significance of pharmacokinetic/pharmacodynamic (PK/PD) parameters of azithromycin (AZM) in tonsillar and respiratory tract infections, we developed original simulation software. As area under the curve over 24 hours divided by the minimum inhibitory concentration (AUC24/MIC) and time over a 24-hour period that the drug concentration exceeds the MIC (t > MIC) are important predictors of the clinical efficacy of macrolides, our software calculates these indices for plasma, tonsil, epithelial lining fluid (ELF), lung tissue (LT) and alveolar macrophages (AM). For an MIC of 0.5 microgram.mL-1, after administration of AZM 500 mg daily for 3 days (tonsillitis) or AZM 500 mg on day 1 and 250 mg daily for the next 4 days (respiratory tract infections) to a 70 kg subject, PK/PD parameters are as follows: AUC24/MIC (h): 9.5 (plasma); 439 (tonsil); 57.5 (ELF); 439 (LT); 1354 (AM); t > MIC is 24 hours in all tissues. Our simulation model illustrates the following: (i) AUC24/MIC values are above the 25-30-hour threshold in S. pneumoniae infection; and (ii) tissue concentrations exceed the MIC for 6 days after the last dose in ELF and for more than 2 weeks in tonsils, LT and AM.  相似文献   

20.
The concentrations of rifampicin in epithelial lining fluid (ELF), human alveolar macrophages (AM), bronchial mucosal biopsies and serum were measured after a single oral dose of 600 mg rifampicin from 15 patients undergoing fibre-optic bronchoscopy. The samples of ELF, AM, the bronchial mucosal biopsies and serum were obtained approximately 2-5 h after dosing. The mean concentrations (mean +/- standard error) were 5.25 mg/L (+/-0.67) in ELF, 7.93 mg/kg (+/-1.61) in bronchial biopsies, 15.48 mg/L (+/-1.41) in serum and 251.8 mg/L (+/-65.92) in alveolar macrophages. These site concentrations exceeded the MIC90 for common respiratory pathogens including Mycobacterium tuberculosis and support the observed clinical efficacy of rifampicin in the treatment of a wide range of respiratory tract infections.  相似文献   

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