title: Colistin and Fusidic Acid, a Novel Potent Synergistic Combination for Treatment of Multidrug-Resistant Acinetobacter baumannii Infections.
abstract: The spread of multidrug-resistant Acinetobacter baumannii (MDRAB) has led to the renaissance of colistin (COL), often the only agent to which MDRAB remains susceptible. Effective therapy with COL is beset with problems due to unpredictable pharmacokinetics, toxicity, and the rapid selection of resistance. Here, we describe a potent synergistic interaction when COL was combined with fusidic acid (FD) against A. baumannii. Synergy in vitro was assessed against 11 MDRAB isolates using disc diffusion, checkerboard methodology (fractional inhibitory concentration index [FICI] of ≤ 0.5, susceptibility breakpoint index [SBPI] of >2), and time-kill methodology (≥2 log10 CFU/ml reduction). The ability of FD to limit the emergence of COL resistance was assessed in the presence and absence of each drug alone and in combination. Synergy was demonstrated against all strains, with an average FICI and SBPI of 0.064 and 78.85, respectively. In time-kill assays, COL-FD was synergistic and rapidly bactericidal, including against COL-resistant strains. Fusidic acid prevented the emergence of COL resistance, which was readily selected with COL alone. This is the first description of a novel COL-FD regimen for the treatment of MDRAB. The combination was effective at low concentrations, which should be therapeutically achievable while limiting toxicity. Further studies are warranted to determine the mechanism underlying the interaction and the suitability of COL-FD as an unorthodox therapy for the treatment of multidrug-resistant Gram-negative infections.
authors.affiliation: Antimicrobial Research Group, Centre for Immunology and Infectious Disease, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom Division of Infection, Barts Health NHS Trust, London, United Kingdom l.m.phee@qmul.ac.uk d.w.wareham@qmul.ac.uk.
authors.forename: Lynette M
authors.initials: LM
authors.lastname: Phee
authors.affiliation: Antimicrobial Research Group, Centre for Immunology and Infectious Disease, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Betts
authors.affiliation: Division of Infection, Barts Health NHS Trust, London, United Kingdom.
authors.forename: Binutha
authors.initials: B
authors.lastname: Bharathan
authors.affiliation: Antimicrobial Research Group, Centre for Immunology and Infectious Disease, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom Division of Infection, Barts Health NHS Trust, London, United Kingdom l.m.phee@qmul.ac.uk d.w.wareham@qmul.ac.uk.
authors.forename: David W
authors.initials: DW
authors.lastname: Wareham
mesh_terms: D000151:Acinetobacter Infections / Q000188:drug therapy*; D040981:Acinetobacter baumannii / Q000187:drug effects*; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D003091:Colistin / Q000627:therapeutic use*; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects*; D004357:Drug Synergism; D004359:Drug Therapy, Combination / Q000379:methods; D005672:Fusidic Acid / Q000627:therapeutic use*; D006801:Humans; D008826:Microbial Sensitivity Tests / Q000379:methods
chemical_list: D000900:Anti-Bacterial Agents; D005672:Fusidic Acid; D003091:Colistin