Activity of levofloxacin in combination with colistin against Acinetobacter baumannii: In vitro and in a Galleria mellonella model

Abstract

Background/Purpose: Treatment of Acinetobacter baumannii infections is challenging owing to widespread multidrug-resistant A. baumannii (MDR-AB) and the lack of novel agents. Although recent data suggest that levofloxacin (LVX) may have unique activity against MDR-AB in combination with colistin (CST), further preclinical work is needed. Methods: We used a A. baumannii type strain ATCC19606, a CST-resistant strain AB19606R, and two clinical isolates (GN0624 and GN1115) of MDR-AB to investigate the in vitro and in vivo efficacy of LVX–CST combination. Synergy studies were performed using the microtiter plate chequerboard assay and time–kill methodology. Inhibitory activity of antibiotics against biofilms and the mutant prevention concentrations were also studied in vitro. A simple invertebrate model (Galleria mellonella) has been used to assess the in vivo activity of antimicrobial therapies. Results: The LVX–CST combination was bactericidal against the CST-susceptible clinical isolate (GN0624). In checkerboard assays, synergy (defined as a fractional inhibitory concentration index of < 0.5) was observed between CST and LVX in GN0624. The combination had antibiofilm properties on the preformed biofilms of four tested strains and could prevent the emergence of CST-resistant A. baumanni. Treatment of G. mellonella larvae infected with lethal doses of A. baumannii resulted in significantly enhanced survival rates when LVX was given with CST compared with CST treatment alone (p < 0.05). Conclusion: In summary, a synergistic or additive effect between CST and LVX was observed in vitro and in vivo against CST-susceptible A. baumannii strains, although not against CST-resistant ones. Keywords: Acinetobacter baumannii, antimicrobial synergy, invertebrate model, levofloxacin, polymyxins