Phase I, Dose-Escalating Study of the Safety and Pharmacokinetics of Inhaled Dry-Powder Vancomycin (AeroVanc) in Volunteers and Patients with Cystic Fibrosis: a New Approach to Therapy for Methicillin-Resistant Staphylococcus aureus

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) has become a significant acute and chronic respiratory pathogen. While vancomycin is effective against MRSA, its relatively poor penetration into lung secretions and dose-limiting renal toxicity make it less effective in the respiratory setting. As inhaled administration of vancomycin would overcome these limitations, we developed a dry powder formulation suitable for inhalation (AeroVanc). Here, we report a phase I, single-dose, dose-escalating study aimed at demonstrating safety and tolerability of AeroVanc. In part I, 18 healthy subjects received a single dose of 16 mg, 32 mg, or 80 mg of AeroVanc. Two subjects also received a 250-mg dose of intravenous vancomycin. In part 2 of the study, 32 mg and 80 mg AeroVanc were administered to subjects with cystic fibrosis as single doses. There were no serious side effects. A small drop in forced expiratory volume in 1 s (FEV1) was observed in 3 subjects with cystic fibrosis, one of whom required salbutamol. Vancomycin was rapidly absorbed after inhalation. Peak and mean plasma concentrations of vancomycin were dose proportional. The average minimum concentration of vancomycin in sputum remained above the usual MIC values for MRSA for up to 24 h (minimum sputum concentration [Cmin], 32-mg dose = 3.05 μg/ml, 80-mg dose = 8.0 μg/ml). In conclusion, AeroVanc was well tolerated and achieved high levels in sputum with a mean systemic absorption of 49%, making it a potential therapeutic strategy for respiratory infection with MRSA.

Optimizing Spray-Dried Porous Particles for High Dose Delivery with a Portable Dry Powder Inhaler

“…Aerovanc (Savara Pharmaceuticals) is intended to treat Gram-positive infections (e.g., methicillin-resistant Staphylococcus aureus, MRSA) in CF patients. The small porous particles were manufactured by spray drying a solution-based liquid feed that contained 83% vancomycin and 17% excipients [ 61 , 62 , 63 ]. The core-shell particles contained vancomycin in the core of the particle with a shell of leucine.…”

Optimizing Spray-Dried Porous Particles for High Dose Delivery with a Portable Dry Powder Inhaler

“…Aerovanc (Savara Pharmaceuticals) is intended to treat gram-positive infections (e.g., methicillin-resistant Staphylococcus aureus, MRSA) in CF patients. The small porous particles were manufactured by spray drying a solution-based liquid feed that contained 83% vancomycin and 17% excipients [62][63][64]. The core-shell particles contained vancomycin in the core of the particle with a shell of leucine.…”

Plasma-Activated Saline Promotes Antibiotic Treatment of Systemic Methicillin-Resistant Staphylococcus aureus Infection

“…MRSA generally exists in the form of a biofilm in the lesion location, and it is not easy for the living immune system to inactivate it [ 6 , 7 , 8 , 9 , 10 , 11 ]. Due to the strong antibiotic resistance, MRSA biofilm is difficult to inactivate with a low concentration of antibiotics, and a higher concentration of antibiotics would cause renal toxicity and are almost impossible to achieve in vivo [ 12 , 13 , 14 , 15 ]. The development and approval of new antibiotics are arduous and antibiotic resistance may emerge soon after the clinical application of new antibiotics, which is shorter than the time required for antibiotic research [ 16 , 17 , 18 ].…”