Steady-state intrapulmonary concentrations of moxifloxacin, levofloxacin, and azithromycin in older adults
Steady-state intrapulmonary concentrations of moxifloxacin, levofloxacin, and azithromycin in older adults
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DOI：
10.1378/chest.125.3.965
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发表时间：
2004-03-01
期刊：
影响因子：
9.6
通讯作者：
Nicolau, DP
中科院分区：
文献类型：
--
作者：
Capitano, B;Mattoes, HM;Nicolau, DP
研究目的：为了确定稳态，细胞外，和细胞内的肺处置的氟沙星（MXF），左氧氟沙星（LEVO），阿奇霉素（AZI）相对于血浆超过24小时dosing interval.Design：随机，多中心，开放标签investigation.Patients：47老年人（平均[+/- SD]年龄，62 +/- 13岁）接受诊断支气管镜检查。干预措施：口服MXF，400 mg，LEVO，500 mg，每日5次，或AZI，500 mg，每日1次，然后250 mg，每日4次。BAL和静脉穿刺完成后4，8，12，或24小时的最后一次dose. Measures和结果：稳态MXF，LEVO和AZI浓度测定血浆，上皮衬里液（ELF），肺泡巨噬细胞（AM）。与血浆相比，所有三种药物的浓度在AM中最高，其次是ELF。血浆浓度与先前报告的这些药物相似。4、8、12和24小时的平均ELF浓度如下：MXF，分别为11.7 +/- 11.9、7.8 +/- 5.1、10.5 +/- 3.7和5.7 +/- 6.3 mug/mL;左旋咪唑分别为15.2 +/- 4.5、10.2 +/- 6.7、6.9 +/- 4.4和2.9 +/- 1.7 μ g/mL;阿齐霉素分别为0.6 +/- 0.4、0.7 +/- 0.4、0.9 +/- 0.5和0.9 +/- 0.7 μ g/mL。4、8、12和24小时的AM浓度如下：MXF，分别为47.7 +/- 47.6、123.3 +/- 126.4、26.2 +/- 19.4和32.8 +/- 16.5 μ g/mL;左旋咪唑，分别为28.5 ± 30.2、26.1 ± 15.7、28.3 ± 12.6和8.2 ± 6.1 μ g/mL;和AZI分别为71.8 ± 50.1、73.8 ± 75.3、155.9 ± 81.3和205.2 ± 256.3 μ g/mL。结论：MXF、LEV和AZI的肺内浓度上级血浆浓度。相对于抑制90%的常见胞内病原体的微生物群体（MIC 90）所需的最低浓度（< 1 μ g/mL），所研究的所有试剂的AM浓度是足够的。这些数据表明，根据AZI目前的最低抑菌浓度曲线，AZI的可达到细胞外浓度不足以可靠地根除肺炎链球菌，而ELF中MXF和LEVO的平均浓度超过肺炎链球菌种群的MIC 90。此外，MXF浓度在所有时间点均超过肺炎链球菌敏感性断点（1.0 μ g/mL），而15个浓度中的2个（13%）在整个给药间隔内未能将LEVO浓度维持在断点（2.0 μ g/mL）以上。
Study objective: To determine the steady-state, extracellular, and intracellular pulmonary disposition of moxifloxacin (MXF), levofloxacin (LEVO), and azithromycin (AZI) relative to that of the plasma over a 24-h dosing interval.Design: Randomized, multicenter, open-label investigation.Patients: Forty-seven older adults (mean [+/- SD] age, 62 +/- 13 years) undergoing diagnostic bronchoscopy. Interventions: Oral administration of MXF, 400 mg, LEVO, 500 mg daily for five doses, or AZI, 500 mg for one dose, then 250 mg daily for four doses. BAL and venipuncture were completed at 4, 8, 12, or 24 h following the administration of the last dose.Measurements and results: Steady-state MXF, LEVO, and AZI concentrations were determined in the plasma, epithelial lining fluid (ELF), and alveolar macrophages (AMs). The concentrations of all three agents were greatest in the AMs followed by the ELF compared to the plasma. Plasma concentrations were similar to those previously reported with these agents. The mean ELF concentrations at 4, 8, 12, and 24 h were as follows: MXF, 11.7 +/- 11.9, 7.8 +/- 5.1, 10.5 +/- 3.7, and 5.7 +/- 6.3 mug/mL, respectively; LEVO, 15.2 +/- 4.5, 10.2 +/- 6.7, 6.9 +/- 4.4, and 2.9 +/- 1.7 mug/mL, respectively; and AZI, 0.6 +/- 0.4, 0.7 +/- 0.4, 0.9 +/- 0.5, and 0.9 +/- 0.7 mug/mL, respectively. The AM concentrations at 4, 8, 12, and 24 h were as follows: MXF, 47.7 +/- 47.6, 123.3 +/- 126.4, 26.2 +/- 19.4, and 32.8 +/- 16.5 mug/mL, respectively; LEVO, 28.5 +/- 30.2, 26.1 +/- 15.7, 28.3 +/- 12.6, and 8.2 +/- 6.1 mug/mL, respectively; and AZI, 71.8 +/- 50.1, 73.8 +/- 75.3, 155.9 +/- 81.3, and 205.2 +/- 256.3 mug/mL, respectively.Conclusions: The intrapulmonary concentrations of MXF, LEV, and AZI were superior to those obtained in the plasma. The AM concentrations of all agents studied were more than adequate relative to the minimum concentration required to inhibit 90% of the organism population (MIC90) of the common intracellular pathogens (< 1 mug/mL). These data indicate that attainable extracellular concentrations of AZI are insufficient to reliably eradicate Streptococcus pneumoniae, based on the agent's current minimum inhibitory concentration profile, whereas the mean concentrations of MXF and LEVO in the ELF exceed the MIC90 of the S pneumoniae population. Moreover, MXF concentrations exceeded the S pneumoniae susceptibility breakpoint (1.0 mug/mL) at all time points, while 2 of 15 concentrations (13%) failed to maintain LEVO concentrations above the breakpoint (2.0 mug/mL) throughout the dosing interval.