Sullivan Bradley P, El-Gendy Nashwa, Kuehl Christopher, Berkland Cory
†Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas 66047, United States.
§Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt.
Mol Pharm. 2015 Aug 3;12(8):2665-74. doi: 10.1021/acs.molpharmaceut.5b00062. Epub 2015 May 6.
Antibiotic multiresistant pneumonia is a risk associated with long-term mechanical ventilation. Vancomycin is commonly prescribed for methicillin-resistant Staphylococcus aureus infections; however, current formulations of vancomycin are only given intravenously. High doses of vancomycin have been associated with severe renal toxicity. In this study, we characterized dry powder vancomyin as a potential inhaled therapeutic aerosol and compared pharmacokinetic profiles of iv and pulmonary administered vancomycin in intubated rabbits through an endotracheal tube system. Cascade impaction studies indicated that using an endotracheal tube, which bypasses deposition in the mouth and throat, increased the amount of drug entering the lung. Bypassing the endotracheal tube with a catheter further enhanced drug deposition in the lung. Interestingly, intubated rabbits administered 1 mg/kg vancomycin via inhalation had similar AUC to rabbits that were administered 1 mg/kg vancomycin via a single bolus iv infusion; however, inhalation of vancomycin reduced Cmax and increased Tmax, indicating that inhaled vancomycin resulted in more sustained pulmonary levels of vancomycin. Collectively, these results suggested that dry powder vancomycin can successfully be delivered by pulmonary inhalation in intubated patients. Furthermore, as inhaled vancomycin is delivered locally to the site of pulmonary infection, this delivery route could reduce the total dose required for therapeutic efficacy and simultaneously reduce the risk of renal toxicity by eliminating the high levels of systemic drug exposure required to push the pulmonary dose to therapeutic thresholds during iv administration.
多重耐药性肺炎是长期机械通气相关的一种风险。万古霉素常用于耐甲氧西林金黄色葡萄球菌感染的治疗；然而，目前的万古霉素制剂仅通过静脉给药。高剂量万古霉素与严重的肾毒性有关。在本研究中，我们将万古霉素干粉表征为一种潜在的吸入性治疗气雾剂，并通过气管插管系统比较了气管插管兔静脉注射和肺部给药万古霉素的药代动力学特征。级联冲击研究表明，使用绕过口腔和咽喉沉积的气管插管可增加进入肺部的药物量。用导管绕过气管插管可进一步增强药物在肺部的沉积。有趣的是，经吸入给予1mg/kg万古霉素的气管插管兔的AUC与经单次静脉推注给予1mg/kg万古霉素的兔相似；然而，吸入万古霉素可降低Cmax并增加Tmax，表明吸入万古霉素可使肺部万古霉素水平更持久。总体而言，这些结果表明，万古霉素干粉可成功地经肺部吸入给药于气管插管患者。此外，由于吸入万古霉素是局部递送至肺部感染部位，这种给药途径可减少治疗有效所需的总剂量，并同时通过消除静脉给药期间将肺部剂量推至治疗阈值所需的高全身药物暴露水平来降低肾毒性风险。
