Antimicrobial efficacy of cinnamaldehyde combined with polymyxin B against carbapenem- polymyxin-resistant Klebsiella pneumoniae.

The global spread of multi-drug-resistant bacteria, including strains resistant to both polymyxin and carbapenems, poses a significant threat to public health, highlighting the need to develop new antimicrobial agents. This study assessed the antimicrobial potential of cinnamaldehyde, alone and in combination with antibiotics, against carbapenem-polymyxin-resistant K. pneumoniae strains (CPR-Kp). The antimicrobial activity was assessed through minimum inhibitory concentration (MIC), checkerboard assay, and survival curve analysis. Cinnamaldehyde showed inhibitory effects (MIC 281 µg/mL), and when combined with polymyxin B, resulted in synergistic effects, effectively overcoming resistance to both polymyxin and carbapenem. Notably, cinnamaldehyde (70 µg/mL) combined with polymyxin B (1 µg/mL) led to a significant reduction in the MIC of polymyxin B, from 64 µg/mL to 1 µg/mL, with a fractional inhibitory concentration index (FICI) of 0.26, indicating synergy. The ZIP synergy score analysis further corroborated these findings, revealing a global synergy score of 32.728, with the highest values observed at cinnamaldehyde concentrations of 70-140 µg/mL in combination with polymyxin B. Similarly, in vivo the combination of cinnamaldehyde (30 or 100 mg/kg) with polymyxin B (2 mg/kg) significantly reduced bacterial loads in blood and peritoneal lavage (p < 0.0001) and improved survival rates. These findings underscore the efficacy of cinnamaldehyde as an adjuvant to polymyxin B in treating infections caused by CPR-Kp. The observed synergistic effect suggests that cinnamaldehyde as a pivotal component in future therapeutic formulations, providing a promising avenue for further research in combating antimicrobial resistance.