Bacteriophage-antibiotic synergy enhances therapeutic efficacy against multidrug-resistant Klebsiella pneumoniae infections

AIMS: This study aims to evaluate the therapeutic efficacy of bacteriophage therapy alone or in combination with antibiotics in the treatment of acute infection caused by multidrug-resistant (MDR) Klebsiella pneumoniae. METHODS AND RESULTS: In this study, we isolated and characterized a lytic bacteriophage vB_Kpn_FOPMU1, which exhibits potent antibacterial activity against K. pneumoniae. Whole-genome sequencing identified vB_Kpn_FOPMU1 as a member of the Przondovirus genus and revealed the presence of key lysis-associated genes, including those encoding endolysin, holin, and Rz-like spanin proteins. In vitro work demonstrated that incubation of bacteriophage and cefotaxime with K. pneumoniae significantly decreased the minimal inhibitory concentration of cefotaxime from 128 to 1 µg ml-1, indicating strong synergistic activity. Using a murine model of acute K. pneumoniae lung infection, we further demonstrated that the combination therapy significantly enhanced bacterial clearance compared to phage monotherapy. This synergistic approach restored sensitivity of K. pneumoniae to cefotaxime, prevented the emergence of phage-resistant bacterial mutants, and achieved superior bacterial eradication from both the lung and blood. Moreover, administration of the phage-antibiotic combination resulted in complete protection of infected mice, with a 100% survival rate, compared to a 60% survival rate observed in animals that received phage monotherapy. Therapeutic application of the bacteriophage-cefotaxime combination resulted in significantly improved lung pathology, characterized by reduced inflammatory cell infiltration and diminished tissue damage, compared to bacteriophage monotherapy. CONCLUSION: Our findings underscore the potential of bacteriophage-antibiotic synergy as a promising therapeutic strategy to combat MDR K. pneumoniae infections and mitigate the risk of phage resistance development.