Evaluation of the safety profile and intrapulmonary pharmacokinetics of intravenous fosfomycin in healthy adults.

UNLABELLED

This Phase 1 trial described the intrapulmonary pharmacokinetics and safety profile of IV fosfomycin in healthy participants Fosfomycin, a broad-spectrum antibiotic mainly used to treat urinary tract infections, is being considered for treatment of more complex conditions, including lung infections, due to the emergence of multidrug-resistant (MDR) organisms. Despite its potential, the pharmacokinetics and safety profile of intravenous (IV) fosfomycin, particularly its penetration into the lower respiratory tract, are unknown. To address this gap, we conducted a Phase 1, open-label trial to assess the safety and pulmonary pharmacokinetics of IV fosfomycin in healthy participants. Thirty-seven healthy volunteers aged 18-45 years received three doses of 6 g IV fosfomycin every 8 hours. Bronchoscopy with bronchoalveolar lavage (BAL) was performed at randomly assigned time points after the third dose. BAL fluid, BAL cell pellets, and blood plasma samples for fosfomycin were analyzed using validated assays of liquid chromatography with tandem mass spectrometry (LC-MS/MS). Adverse events (AEs) were assessed. Fosfomycin exhibited penetration into alveolar macrophages (AM) at a rate of 16.8% and into the extracellular lining fluid (ELF) at 30.8%. Mean AM fosfomycin concentration ranged from 14.8 to 32 μg/mL, while the mean ELF concentration ranged from 15.7 to 82.5 μg/mL. All participants experienced at least one treatment-emergent adverse event (TEAE), mostly mild/grade 1, with no serious adverse events (SAEs) reported. Intravenous fosfomycin effectively penetrates both the extracellular (ELF) and intracellular (AM) compartments of the lower respiratory tract in healthy participants. The overall tolerability of IV fosfomycin was favorable, suggesting its potential as an effective antibacterial treatment for lower respiratory tract infections.

CLINICAL TRIALS

This study is registered with ClinicalTrials.gov as NCT03910673.