在健康肺的机械通气雌性小猪中，万古霉素雾化吸入比静脉注射能提供更高的肺组织浓度。

Nebulization of Vancomycin Provides Higher Lung Tissue Concentrations than Intravenous Administration in Ventilated Female Piglets with Healthy Lungs.

机构信息

From the Laboratory of Anesthesiology, School of Medicine, São Paulo University, São Paulo, Brazil (C.L.d.M.M., M.J.C.C., D.R.R.M., J.O.C.A., D.A.O.) Laboratory of Clinical and Experimental Pharmacology, Department of Pharmacology, Institute of Biological Sciences, Federal University of Juiz de Fora, Juiz de Fora, Brazil (J.W.L.N., A.C.R.) Anesthesiology Division, School of Medicine, Pontifical Catholic University of Chile, Santiago de Chile, Chile (L.I.C.) Sorbonne University, Multidisciplinary Intensive Care Unit, Pitié-Salpêtrière Hospital, Public Assistance Hospitals of Paris, Paris, France (A.M., J.-J.R.).

出版信息

Anesthesiology. 2020 Jun;132(6):1516-1527. doi: 10.1097/ALN.0000000000003171.

DOI:10.1097/ALN.0000000000003171

PMID:32053565

Abstract

BACKGROUND

Intravenous vancomycin is used to treat ventilator-associated pneumonia caused by methicillin-resistant Staphylococcus aureus, but achieves high rates of failure. Vancomycin nebulization may be efficient to provide high vancomycin lung tissue concentrations. The aim of this study was to compare lung tissue and serum concentrations of vancomycin administered intravenously and by aerosol in mechanically ventilated and anesthetized healthy piglets.

METHODS

Twelve female piglets received a single intravenous dose of vancomycin (15 mg/kg) and were killed 1 (n = 6) or 12 h (n = 6) after the end of administration. Twelve piglets received a single nebulized dose of vancomycin (37.5 mg/kg) and were killed 1 (n = 6) or 12 h (n = 6) after the end of the aerosol administration. In each group, vancomycin lung tissue concentrations were assessed on postmortem lung specimens using high-performance liquid chromatography. Blood samples were collected for serum vancomycin concentration measurement 30 min and 1, 2, 4, 6, 8, and 12 h after the end of vancomycin administration. Pharmacokinetics was analyzed by nonlinear mixed effect modeling.

RESULTS

One hour after vancomycin administration, lung tissue concentrations in the aerosol group were 13 times the concentrations in the intravenous group (median and interquartile range: 161 [71, 301] μg/g versus 12 [4, 42] μg/g; P < 0.0001). Twelve hours after vancomycin administration, lung tissue concentrations in the aerosol group were 63 (23, 119) μg/g and 0 (0, 19) μg/g in the intravenous group (P < 0.0001). A two-compartment weight-scaled allometric model with first-order absorption and elimination best fit serum pharmacokinetics after both routes of administration. Area under the time-concentration curve from 0 to 12 h was lower in the aerosol group in comparison to the intravenous group (56 [8, 70] mg · h · l vs. 121 [103, 149] mg · h · l, P = 0.002). Using a population model, vancomycin bioavailability was 13% (95% CI, 6 to 69; coefficient of variation = 85%) and absorption rate was slow (absorption half life = 0.3 h).

CONCLUSIONS

Administration of vancomycin by nebulization resulted in higher lung tissue concentrations than the intravenous route.

摘要

背景

静脉万古霉素用于治疗耐甲氧西林金黄色葡萄球菌引起的呼吸机相关性肺炎，但成功率较高。万古霉素雾化可能有效提供高万古霉素肺组织浓度。本研究旨在比较静脉和雾化给药后机械通气和麻醉健康小猪的肺组织和血清万古霉素浓度。

方法

12 只雌性小猪接受静脉注射万古霉素（15mg/kg）单次剂量，在给药结束后 1 小时（n=6）或 12 小时（n=6）处死。12 只小猪接受雾化万古霉素（37.5mg/kg）单次剂量，在雾化给药结束后 1 小时（n=6）或 12 小时（n=6）处死。在每组中，使用高效液相色谱法在死后肺标本上评估万古霉素的肺组织浓度。在万古霉素给药结束后 30 分钟和 1、2、4、6、8 和 12 小时收集血样以测量血清万古霉素浓度。通过非线性混合效应模型分析药代动力学。

结果

万古霉素给药后 1 小时，雾化组肺组织浓度为静脉组的 13 倍（中位数和四分位距：161[71,301]μg/g 与 12[4,42]μg/g；P<0.0001）。万古霉素给药后 12 小时，雾化组肺组织浓度为 63（23,119）μg/g，静脉组为 0（0,19）μg/g（P<0.0001）。两室权重比例模型，具有一级吸收和消除，最适合两种给药途径的血清药代动力学。与静脉组相比，雾化组 0 至 12 小时的时间浓度曲线下面积较低（56[8,70]mg·h·l 与 121[103,149]mg·h·l，P=0.002）。使用群体模型，万古霉素生物利用度为 13%（95%CI，6 至 69；变异系数=85%），吸收速度较慢（吸收半衰期=0.3h）。