Evaluation of Bacteriophage and Antibiotic Synergy Against Carbapenem-Resistant Klebsiella pneumoniae Clinical Isolates

초록

The global rise of carbapenem-resistant Klebsiella pneumoniae (CRKP) poses a serious threat to public health due to limited therapeutic options and high mortality rates. Bacteriophage (phage) therapy has emerged as a promising alternative; however, its effectiveness is often compromised by the rapid development of phage resistance. In this study, we investigated the synergistic potential of phage- antibiotic combination therapy against CRKP. Four phages―vB_KpnM_W9-2, vB_KpnM_W10-2, vB_KpnM_W12-3, and vB_KpnP_W17―were isolated and characterized for adsorption rate, replication dynamics, and environmental stability. Among them, vB_KpnP_W17 exhibited the most favorable adsorption kinetics and stability under various stress conditions. Synergistic interactions between phages and five antibiotics (colistin, meropenem, ciprofloxacin, amikacin, and tigecycline) were assessed in vitro using checkerboard assays against two CRKP clinical isolates. Phage-antibiotic combinations, particularly vB_KpnP_W17 with ciprofloxacin, significantly reduced the minimum inhibitory concentrations of the antibiotics and showed strong synergistic effects. In vivo mouse infection models further confirmed the therapeutic benefit, with repeated administration of the combination treatment resulting in a significant improvement in survival. Overall, these findings suggest that phage-antibiotic combinatorial therapy is a potent and viable strategy to combat CRKP infections and mitigate antibiotic resistance.

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