Zidovudine in synergistic combination with fosfomycin: an in vitro and in vivo evaluation against multidrug-resistant Enterobacterales.

Abstract Background MDR Enterobacterales are a priority health issue with few options. Recently, fosfomycin has been reconsidered for MDR bacterial infections. Zidovudine, licensed for HIV, has unexploited antibacterial properties and has been considered as repurposing antibiotic. The aim of the present study was to assess the effect of fosfomycin + zidovudine combination against clinical MDR Enterobacterales. Methods MIC and checkerboard assays for 36 MDR Enterobacterales strains were performed. In addition, fosfomycin-resistant strains were evaluated using time-kill assay and in vivo Galleria mellonella infection model. Results Zidovudine and fosfomycin MICs ranged between 0.06 - > 64 mg/L and 0.125 - > 512 mg/L, respectively. A synergistic effect (FIC index ≤ 0.5) was observed in 25 strains and no antagonistic effect was observed in the remaining isolates. For 7 out of 8 fosfomycin-resistant strains (MIC > 32 mg/L), zidovudine combination was able to restore fosfomycin-susceptibility. These results were confirmed by time-kill assays. Fosfomycin + zidovudine presented greater larval survival (20-50%) than monotherapy. Discussion Synergistic activity was observed for fosfomycin + zidovudine in 69.4% of the tested strains. In vivo experiments confirmed the enhanced effectiveness of the combination. Zidovudine concentrations tested here can be reached in human serum using the actual licensed dosage, therefore this combination deserves further clinical investigations.