Antimicrobial activity of ceftibuten/polymyxin B combination against polymyxin/carbapenem-resistant Klebsiella pneumoniae

Abstract

Objectives To evaluate the synergistic effect of a ceftibuten and polymyxin B combination and to determine its capacity to overcome polymyxin B resistance in polymyxin/carbapenem-resistant (PC-R) Klebsiella pneumoniae. Methods To investigate the combination’s antibacterial efficacy, antimicrobial susceptibility tests using broth microdilution methods, chequerboard assays and time–kill testing were performed. Antibiofilm activity was also assessed. The treatment’s effect on the bacterial cell membrane was examined by quantifying intracellular protein leakage and conducting scanning electron microscopy. Haemocompatibility tests were conducted to evaluate toxicity. Additionally, an infection model was established using Swiss mice to assess in vivo antimicrobial activity. Results The ceftibuten/polymyxin B combination demonstrated synergistic effects against several PC-R strains of K. pneumoniae, as determined by the FIC index (FICI) values, which ranged from 0.15 to 0.37. This combination was efficacious, exhibiting bactericidal activity at twice the MIC. Ceftibuten/polymyxin B also demonstrated antibiofilm activity. Additionally, ceftibuten/polymyxin B neither damaged the bacterial membrane nor exhibited haemolytic activity. Based on these findings, the in vivo therapeutic potential was investigated and it was found that ceftibuten/polymyxin B significantly decreased the bacterial load in the peritoneal lavage fluid of mice, revealing its effectiveness in treating infections caused by PC-R K. pneumoniae. Conclusions The ceftibuten/polymyxin B combination exhibited synergistic effects in vitro and in vivo, and thus might be a promising therapeutic alternative for treating PC-R K. pneumoniae infections. As the combination was efficacious in preclinical models, researchers may further investigate its potential in clinical studies.