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Klebsiella pneumoniae  has emerged as a major clinical and public health threat owing to the increasing prevalence of healthcare-associated infections caused by multidrug-resistant or extensively drug-resistant strains. However, increasing antibiotic resistance and the absence of clinically effective antimicrobial agents make combination therapy an urgent need. This study investigated the anti-microbial activity of SPR741, a polymyxin B derivative, in combination with macrolide antibiotics (erythromycin and clarithromycin), against extensively drug-resistant and pandrug-resistant  K. pneumoniae.  Monotherapy, double, and triple combination therapies were performed to identify the most effective treatment combination using  in vitro  checkerboard, time-killing kinetics. Furthermore, we evaluated the biofilm eradication and persister cell-killing activity of these combinations using laser confocal microscopy and colony forming unit counting. In addition, a neutropenic mouse thigh infection model was used to assess the therapeutic efficacy and toxicity of the triple antibiotic combination against pandrug-resistant  K. pneumoniae in vivo . Our results suggested that SPR741 combined with macrolides exhibited strong synergistic antibacterial activity against extensively drug-resistant and pandrug-resistant  K. pneumoniae . These antibiotic combinations could also effectively eradicate highly resistant bacterial biofilms and persister cells  in vitro  and demonstrate considerable efficacy and low toxicity  in vivo . In summary, our findings indicated that SPR741, in combination with macrolide antibiotics (double or triple combination), has the potential to serve as a novel treatment option against drug-resistant  K. pneumoniae  -related infections.

frontiers in cellular and infection microbiology

SPR741, Double- or Triple-Combined With Erythromycin and Clarithromycin, Combats Drug-Resistant Klebsiella pneumoniae, Its Biofilms, and Persister Cells