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

• Published in: Antimicrobial agents and chemotherapy Vol. 64; no. 3
• Main Authors: Waterer, Grant, Lord, John, Hofmann, Thomas, Jouhikainen, Taneli
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 21.02.2020
• Subjects: Administration, Inhalation; Adolescent; Adult; Anti-Bacterial Agents - blood; Anti-Bacterial Agents - pharmacokinetics; Anti-Bacterial Agents - pharmacology; Cystic Fibrosis - blood; Cystic Fibrosis - drug therapy; Cystic Fibrosis - microbiology; Dry Powder Inhalers; Experimental Therapeutics; Female; Forced Expiratory Volume - drug effects; Forced Expiratory Volume - physiology; Humans; Male; Methicillin-Resistant Staphylococcus aureus - drug effects; Methicillin-Resistant Staphylococcus aureus - growth & development; Microbial Sensitivity Tests; Middle Aged; Opportunistic Infections - blood; Opportunistic Infections - drug therapy; Patient Safety; Powders; Staphylococcal Infections - blood; Staphylococcal Infections - drug therapy; Vancomycin - blood; Vancomycin - pharmacokinetics; Vancomycin - pharmacology; vancomycin; cystic fibrosis; MRSA; inhaled
• DOI: 10.1128/AAC.01776-19
• ISSN: 0066-4804; 1098-6596

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). 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 (FEV 1 ) 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 [ C min ], 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.