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Published on: February 26, 2021
Pulmonary Delivery of Vancomycin Dry Powder Aerosol to Intubated Rabbits
Bradley P Sullivan1, Nashwa El-Gendy1,2, Christopher Kuehl1
1†Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas 66047, United States.
Abstract:
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.
Insights
Inhaled dry powder vancomycin shows promise for treating resistant pneumonia in ventilated patients. This method achieved sustained lung levels, potentially reducing dose and kidney toxicity compared to IV vancomycin.
Area of Science:
- Pulmonary Drug Delivery
- Pharmacokinetics
- Infectious Diseases
Background:
- Antibiotic-resistant pneumonia is a significant risk for patients on long-term mechanical ventilation.
- Current intravenous vancomycin formulations for methicillin-resistant Staphylococcus aureus (MRSA) infections can cause severe renal toxicity due to high systemic doses.
- There is a need for safer and more effective vancomycin delivery methods for pulmonary infections.
Purpose of the Study:
- To characterize dry powder vancomycin as an inhaled therapeutic aerosol.
- To compare the pharmacokinetic profiles of intravenous (IV) versus pulmonary-administered vancomycin in intubated rabbits.
- To evaluate the potential of inhaled vancomycin to reduce dose and systemic toxicity.
Main Methods:
- Dry powder vancomycin was formulated as an aerosol for pulmonary delivery.
- Pharmacokinetic studies were conducted in intubated rabbits comparing IV and inhaled vancomycin administration via an endotracheal tube system.
- Cascade impaction was used to assess drug deposition in the lungs, with and without a catheter bypassing the endotracheal tube.
Main Results:
- Using an endotracheal tube increased lung drug deposition by bypassing the upper airway.
- Further bypassing the endotracheal tube with a catheter enhanced lung drug deposition.
- Inhaled vancomycin (1 mg/kg) resulted in similar area under the curve (AUC) as IV vancomycin (1 mg/kg) but with a reduced peak concentration (Cmax) and increased time to peak concentration (Tmax), indicating sustained pulmonary levels.
Conclusions:
- Dry powder vancomycin can be effectively delivered via pulmonary inhalation in intubated patients.
- Inhaled vancomycin provides sustained local drug levels in the lungs.
- This delivery route may reduce the required total dose and mitigate renal toxicity associated with high systemic IV vancomycin exposure.
