Phage-antibiotic synergy to combat multidrug resistant strains of Gram-negative ESKAPE pathogens

Bacteriophage-antibiotic-synergy (PAS) was investigated to target Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter baumannii and Enterobacter cloacae. Whole genome sequencing indicated that bacteriophage KPW17 targeting K. pneumoniae, clustered with genus Webervirus, ECSR5 targeting E. cloacae clustered with Eclunavirus, PAW33 targeting P. aeruginosa clustered with Bruynoghevirus, while ABTW1 targeting A. baumannii clustered with Vieuvirus. PAS analysis showed that the combination of ciprofloxacin (CIP) and levofloxacin (LEV) with PAW33 resulted in the synergistic eradication of all tested P. aeruginosa strains. Similarly, the combined use of doripenem (DOR) and LEV with KPW17 resulted in the synergistic eradication of the environmental and clinical K. pneumoniae strains, while the combined use of DOR and gentamicin (CN) with ECSR5 was synergistic against the clinical E. cloacae NCTC 13406. Gentamicin with ECSR5, however, only exhibited an additive effect for E. cloacae 4L, while ABTW1 with piperacillin-tazobactam (TZP) and imipenem (IPM) resulted in an indifferent interaction between the bacteriophage and tested antibiotics against the clinical A. baumannii AB3, i.e., the activity of the combination is equal to the activity of most active agent. Thus, while the observed PAS may offer an opportunity for the re-introduction or more efficient application of certain antibiotics to combat antibiotic resistance, extensive research is required to determine the optimal phage-antibiotic combinations, dosages and treatment regiments.