An alternative strategy for combination therapy: Interactions between polymyxin B and non-antibiotics

• Published in: International journal of antimicrobial agents 2019-01, Vol.53 (1), p.34-39
• Main Authors: Otto, Robin G., van Gorp, Elke, Kloezen, Wendy, Meletiadis, Joseph, van den Berg, Sanne, Mouton, Johan W.
• Format: Article
• Language: English
• Subjects: Antibiotic resistance; Antibiotic/non-antibiotic combinations; Checkerboard assay; Drug synergy; Polymyxin B; Screening test
• ISSN: 0924-8579; 1872-7913
• DOI: 10.1016/j.ijantimicag.2018.09.003

•Fourteen non-antibiotics showed synergistic interaction with polymyxin B.•Synergistic effects were mostly found for antidepressant drugs.•Spironolactone displayed synergism in vitro at clinically relevant concentrations.•Synergism was observed against Acinetobacter baumannii, Escherichia coli and Klebsiella pneumoniae isolates. Antimicrobial resistance is increasing and few new antibiotics are in the development pipeline. Alternative strategies to treat infectious diseases, such as combination therapy, are urgently needed. Polymyxin B is a neglected and disused antibiotic with moderate antibacterial activity. In this study, we aimed to find synergistic interactions between polymyxin B and a wide range of non-antibiotics (non-ABs) to improve its efficacy. Thirty non-AB compounds from various drug classes were screened for synergistic potential with sub-minimum inhibitory concentrations (MICs) of polymyxin B in an agar diffusion assay against Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa (3 isolates per species). Potential candidates were further studied in in vitro checkerboard assays, up to 5 isolates per species, using optical density to assess growth. Interactions were assessed with fractional inhibitory concentration index (FICi) analysis and surface response analysis with Loewe, Bliss and Highest Single Agent analysis using the Combenefit program. Twenty non-ABs enhanced polymyxin B activity in the agar diffusion test in one or more species. Of these, three showed a consistent synergistic effect (FICi ≤ 0.5) in the checkerboard assay for at least one species: citalopram, sertraline and spironolactone. Surface response analyses were largely in concordance, and further assessment showed only spironolactone was synergistic with polymyxin B at clinically relevant levels. The screening strategy used showed consistent synergism in vitro between polymyxin B and some non-ABs for A. baumannii, E. coli and K. pneumoniae. The synergistic interactions found merit further exploration as alternative strategies for difficult-to-treat infections.