Composite particle formulations of colistin and meropenem with improved in-vitro bacterial killing and aerosolization for inhalation

Abstract

Antibiotic combination therapy is promising for the treatment of lower respiratory tract infections caused by multi-drug resistant Gram-negative pathogens. Inhaled antibiotic therapy offers the advantage of direct delivery of the drugs to the site of infection, as compared to the parenteral administrations. In this study, we developed composite particle formulations of colistin and meropenem. The formulations were characterized for particle size, morphology, specific surface area, surface chemical composition, in-vitro aerosolization performance and in-vitro antibacterial activity. The combinations demonstrated enhanced antibacterial activity against clinical isolates of Acinetobacter baumannii N16870 and Pseudomonas aeruginosa 19147, when compared with antibiotic monotherapy. Spray-dried meropenem alone showed a poor aerosolization performance as indicated by a low fine particle fraction (FPF) of 32.5 ± 3.3%. Co-spraying with colistin improved the aerosolization of meropenem with up to a two-fold increase in the FPF. Such improvements in aerosolization can be attributed to the enrichment of colistin on the surface of composite particles as indicated by X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS), and the increases in particle porosity. Intermolecular interactions between colistin and meropenem were observed for the combination formulations as measured by FT-IR. In conclusion, our results show that co-spray drying with colistin improves the antibacterial activity and aerosol performance of meropenem and produces a formulation with synergistic bacterial killing.

Colistin Resistance among Enterobacteriaceae Isolated from Clinical Samples in Gaza Strip

“…Colistin is considered the last-line drug for MDR Gram-negative bacteria (GNB) [ 3 ], and it is often used for treatment of respiratory infections caused by MDR-GNB. In recent years, there has been a marked increase in the incidence of colistin-resistant infections [ 4 ].…”

Understanding the Impacts of Surface Compositions on the In-Vitro Dissolution and Aerosolization of Co-Spray-Dried Composite Powder Formulations for Inhalation

“…Such heterogeneous surface distributions may have significant impact on dispersion behavior due to changes in particle density, morphology and surface energy, which have been investigated extensively. (48, 53–55) This study focuses on effects of such heterogeneous surface distributions on dissolution behavior of composite particles. Since wetting and dissolution of particles begin at the surface of the particles; the surface composition can have a dominating effect on the dissolution of the particle formulation (56).…”

Simultaneous Particle Size Reduction and Homogeneous Mixing to Produce Combinational Powder Formulations for Inhalation by the Single-Step Co-Jet Milling

“…Such similar FPF and deposition patterns in each co-jet milled formulation confirmed the formation of relatively homogeneous mixtures, despite very different aerosolization behavior of 2 jet-milled pure drugs; though such similarity in deposition patterns for 2 drugs does not reach the same level to the co-spray-dried particles, which incorporate 2 drugs in a single particle. 13,[33][34][35] Another possibility is that 2 jet-milled drugs form preferential agglomerates (such as colistin-ciprofloxacin agglomerates over colistin-colistin and ciprofloxacin-ciprofloxacin agglomerates) according to the loaded drug ratios.…”