title: Tailored Antibiotic Combination Powders for Inhaled Rotational Antibiotic Therapy.
abstract: Respiratory lung infections due to multidrug-resistant (MDR) superbugs are on a global upsurge and have very grim clinical outcomes. Their MDR profile makes therapeutic options extremely limited. Although a highly toxic antibiotic, colistin, is favored today as a "last-line" therapeutic against these hard-to-treat MDR pathogens, it is fast losing its effectiveness. This work therefore seeks to identify and tailor-make useful combination regimens (that are potentially rotatable and synergistic) as attractive alternative strategies to address the rising rates of drug resistance. Three potentially rotatable ternary dry powder inhaler constructs (each involving colistin and 2 other different-classed antibiotics chosen from rifampicin, meropenem, and tigecycline) were identified (with distinct complementary killing mechanisms), coformulated via spray drying, evaluated on their aerosol performance using a Next-Generation Impactor and tested for their efficacies against a number of MDR pathogens. The powder particles were of respirable size (d50, 3.1 ± 0.3 μm-3.4 ± 0.1 μm) and predominantly crumpled in morphology. When dispersed via a model dry powder inhaler (Aerolizer(®)) at 60 L/min, the powders showed concomitant in vitro deposition with fine particle fractions of ∼53%-70%. All formulations were successfully tested in the laboratory to be highly effective against the MDR pathogens. In addition, a favorable synergistic interaction was detected across all 3 formulations when tested against MDR Pseudomonas aeruginosa.
authors.affiliation: Institute of Chemical and Engineering Sciences, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore; Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore, Singapore.
authors.forename: Sie Huey
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Laboratory Medicine, National University Hospital, Singapore, Singapore.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Teo
authors.affiliation: Institute of Chemical and Engineering Sciences, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore. Electronic address: desmond_heng@ices.a-star.edu.sg.
authors.forename: Desmond
authors.initials: D
authors.lastname: Heng
authors.affiliation: Institute of Chemical and Engineering Sciences, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore.
authors.forename: Wai Kiong
authors.initials: WK
authors.lastname: Ng
authors.affiliation: Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore, Singapore; School of Materials Science and Engineering, Nanyang Technological University, Singapore, Singapore.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Institute of Chemical and Engineering Sciences, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore; Department of Chemical and Biomolecular Engineering, National University of Singapore, Singapore, Singapore. Electronic address: reginald_tan@ices.a-star.edu.sg.
authors.forename: Reginald B H
authors.initials: RB
authors.lastname: Tan
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols / Q000008:administration & dosage / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects; D024901:Drug Resistance, Multiple, Bacterial; D004357:Drug Synergism; D058995:Dry Powder Inhalers; D006801:Humans; D010316:Particle Size; D011208:Powders
chemical_list: D000336:Aerosols; D000900:Anti-Bacterial Agents; D011208:Powders
keywords: combinatorial therapy; dry powder inhaler; formulation; particle size; powder technology; resistant bacteria; solid state; spray drying; superbugs; synergy